EP2699545B1 - Novel amino-pyrroline derivatives, and use thereof in the prevention and/or treatment of metabolic syndrome - Google Patents

Description

The present invention relates to novel amino-pyrrolinic derivatives, their use in the prevention and / or treatment of metabolic syndrome.

The metabolic syndrome, also called syndrome X or dysmetabolic syndrome, consists of a set of cardiovascular symptoms, including arterial hypertension, and metabolic (hypercholesterolemia, insulin resistance, glucose intolerance, abdominal obesity) ( Reaven, G, M. 1988. Reading Banting 1988 ; Role of insulin resistance in human disease. Diabetes 37: 1595-1607 ). The meeting of all these symptoms is unanimously recognized as constituting a major cardiovascular and metabolic risk factor. Complications of this metabolic syndrome include atherosclerosis, coronary heart disease, kidney failure, heart failure, diabetes, obesity. The prevalence of this risk factor is still variable across countries. It nevertheless tends to settle around the world around 30% of the general population. Its rapid development is extremely important and poses major public health problems.

The present drug therapy of the metabolic syndrome consists of drug combinations consisting of drugs each acting on only one element of the metabolic syndrome which contains between 3 and 6: antihypertensive drugs (sometimes several associated) in combination with hypoglycemic drugs (sometimes several associates) in combination with lipid-lowering drugs (sometimes several associates).

These combinations generate many adverse effects and some, such as statins, are very expensive.

Although several studies have shown that the metabolic syndrome is associated with sympathetic hyperactivity measured by an increase in Muscular Nervous Sympathetic Activity (MSNA) even in the absence of arterial hypertension ( Huggett RJ; Burns J .; Mackintosh AF; Mary DASG Sympathetic Neural Activation in Nondiabetic Metabolic Syndrome and Its Further Augmentation by Hypertension Hypertension, 2004, 44: 847-852 ), no currently available drug, able to inhibit the sympathetic system, is proposed to treat the metabolic syndrome and its consequences.

Imidazoline receptors (IRs) are involved in several biological regulatory systems. The main one is the regulation, by the sympathetic nervous system, of the arterial pressure ( Bousquet, P .; Feldman, J. Drugs Acting on Imidazoline Receptors: a Review of their Pharmacology, their Use in Blood Pressure Control, and their Potential Interest in Cardioprotection. Drugs 1999, 58, 799-812 ; Head, G. A ,; Mayorov, DN Imidazoline Receptors, Novel Agents and Therapeutic Potential. Cardiovasc. Hematol. Med Agents. Chem. 2006, 4, 17-32 ).

They are also involved in other physiopathological functions such as insulin secretion ( Chan, SLF Clonidine-displacing Substance and its Putative Role in Control of Insulin Secretion: A Minireview. Gen. Pharmacol. 1998, 31, 525-529 ), regulation of intraocular pressure ( Chu, T. C .; R ,, S. R ,; Ogidigben, M. J .; Potter, ED Potential Mechanisms of Moxonidine-Induced Ocular Hypotension: Role of Norepinephrine. J. Ocul. Pharmaco /. Ther. 1997, 13, 489-496 ) and heart rate control ( Roegel, J. C .; from Jong, W .; Monassier, L .; Feldman, J .; Bousquet, P. Comparative Effects of Idazoxan, Prazocine and Yohimbine on Coronary Ligation-induced Arrhythmias in Spontaneously Hypertensive Rats. J. Cardiovasc. Pharmaco /. 1996, 27, 226-234 ).

IRs are classified into three main subtypes RI ₁ . RI ₂ and RI ₃ . The first subtype RI ₁ is located in the rostro-ventrolateral part (RVLM) of the brainstem and is involved in the central regulation of cardiovascular function

RI ₁ is sensitive to clonidine and other imidazoline compounds but not to catecholamines and are therefore different from α ₂ (Rα ₂ A) adrenergic receptors.

Agmatine, "clonidine displacing substances" and harmane are endogenous ligands of RI ₁ .

RI ₂ is insensitive to clonidine but sensitive to idazoxan. IRs ₂ are subdivided into two subtypes according to their affinity for amiloride ( Tesson, F .; Prib-Buus, C .; Lemoine, A ,; Pegorier, J. P .; Parini, A. Subcellular Distribution of Imidazoline-Guanidinium Receptive Sites in Human and Rabbit Liver. Major Localization to the Mitochondrial Outer Membrane. J. Biol. Chem. 1991, 266, 155-160 ).

A third subtype, RI ₃ , has been added to the classification and is involved in the regulation of insulin ( Englen, R. M .; Hudson, A. L .; Kendall, D.A. Nutt, D. J .; Morgan, N. G .; Wilson, V. G .; Dillon, MP 'Seeing Through a Darkly Glass': Casting Light on Imidazoline 'I' Sites. Trends Pharmaco /. Sci. 1998, 19, 381-390 ).

Clonidine is the leading compound of the first generation of antihypertensive drugs, acting centrally. It binds to both RI ₁ and Rα ₂ A. Its side effects, sedation in particular, are clearly due to the activation of Rα ₂ A (De Sarro, G. B, Ascioti, C, Froio , F, Libri, V, Nistico, G. Evidence that Locus Coeruleus is the Site where Clonidine and Drugs Acting at α ₁ - and α ₂ - Adrenoceptors Affect Sleep and Arousal Mechanisms. Br. J. Pharmacol. 1987, 90, 675-685 ).

Drugs such as moxonidine and rilmenidine have a selectivity for RI ₁ compared to Rα ₂ A because they have a lower affinity for Rα ₂ A and therefore cause fewer side effects in hypertensive patients.

Until recently, the lack of selective hypotensive drugs of IR has greatly slowed down research on these receptors.

On the one hand, imidazolinic hypotensive drugs such as clonidine and its analogs are all "hybrid" drugs since they bind to both RI ₁ and Rα ₂ A.

On the other hand, the few compounds so far highly selective for RI ₁ such as AGN192403 ( Munk, S. A ,; Lai, R. K .; Burke, J. E .; Arasasingham, P. N .; Kharlamb, A. B .; Manlapaz, C. A ,; Padillo, E. U .; Wijono, M. K .; Hasson, D. W .; Wheeler, L. A .; Garst, ME Synthesis and Pharmacologic Evaluation of 2-endo-Amino-3-exo-isopropylbicyclo [2,2,1] heptane: Potent Imidazoline Receptor Specific Agent. J. Med. Chem 1996, 39, 1193-1195 ), tracizoline and benazoline (Pigini, M, Bousquet, P, Carotti, A, Dontenwill, M, Giannella, M, Moriconi, R, Piergentili, A, Quaglia, W, Tayebati, S. K, Brasili, L. Imidazoline Receptors: Qualitative Structure-Activity Relationships and the Discovery of Tracizoline and Benazoline. Unprecedented Selectivity. Bioorg. Med. Chem. 1997, 5, 833-841 ) do not change the blood pressure or change it little.

Moreover, there are several compounds that are selective for RI ₁ compared to Rα ₂ A but that are not selective with respect to RI ₂ , such as S23757 ( Anastasiadou, M .; Danoun, S ,; Crane, L .; Baziard-Mouysset, G .; Payard, M .; Caignard, D, -H ,; Rettori, M, -C; Renard, P. Synthesis and Pharmacological Evaluation of Imidazoline Sites I1 and I2 Selective Ligands. Bioorg. Med. Chem. 2001, 9, 585-592 ) and PMS 952 ( Ye, H. F .; Dive, G ,; Dehareng, D .; Heymans, F .; Godfroid, JJ Structure-Activity Relationship on Adrenoceptors and Imidazoline-Preferring Binding Sites (I1,2-PBS). Part 1: Weak Intramolecular H-bond and Conformational Flexibility in a New I1-PBS-Selective Imidazoline Analogue, trans1- (4'-5'-Dihydro-1'H-imidazol-2'-yl) methyl-2-hydroxyindan ( PMS 952). Bioorg. Med. Chem. 2000, 8, 1861-1869 ).

Recently, selective compounds of RI ₁ , LNP 911 and LNP 906, which are aminopyrrolins unlike the other compounds described above and have nanomolar affinities for the RI ₁ receptor, have been developed respectively as a radioligand and photoaffinity radioligand. ( Greney, H .; Urosevic, D .; Schann, S ,; Dupuy, L .; Bruban, V .; Ehrhardt, J, -D; Bousquet, P .; Dontenwill, M. [125 I] 2- (2-chloro-4-iodo-phenylamino) -5-methyl-pyrroline (LNP911), High-Affinity Radioligand Selective for Imidazoline Receptors. Mol. Pharmaco /. 2002, 62, 181-191 ), but do not have a hypotensive effect. LNP 911 behaves more like an antagonist while LNP 906 which is a photoactivatable ligand is unusable in in vivo experiments.

Therefore, there is a need to develop compounds which are selective for IN ₁ , so as to avoid side effects, which still have hypotensive activity and which can be used as monotherapy in the metabolic syndrome.

An object of the present invention is to provide selective compounds of RI ₁ thus not interacting with little or Rα ₂ A and RI _2. Moreover, the compounds are agonists of RI _1.

Another object of the invention is to provide active drugs in the metabolic syndrome, used as monotherapy and not having the side effects of current drugs.

Another object of the invention is to provide pharmaceutical compositions comprising said active drugs.

dans laquelle :

1. a) soit R12 représente H, et
   • R1 et R2 représentent indépendamment les uns des autres :
     • un halogène, un alkyle en C1 à C8 linéaire ou ramifié, un alcène en C2-C8, un alcoxy en C1 à C8 linéaire ou ramifié, un cycloalkyle en C3-C6, un bicycloalkyle en C5-C6, une chaîne polyéther, un perfluoroalkyle en C1-C5, un acyle en C1-C8, OH, SH, une amine primaire, secondaire ou tertiaire, CN, CO₂H CO₂R' dans lequel R' est un alkyle linéaire ou ramifié en C1-C8, ou un cycloalkyle en C3-C6, ou
   • R1 et R2 forment ensemble un cycle en C5,
   • R3, R4 et R5 représentent indépendamment les uns des autres :
     • un hydrogène, un halogène, un alkyle en C1 à C8 linéaire ou ramifié, un alcène en C2-C8, un alcoxy en C1 à C8 linéaire ou ramifié, un cycloalkyle en C3-C6, un bicycloalkyle en C5-C6, une chaîne polyéther, un perfluoroalkyle en C1-C5, un acyle en C1-C8, OH, SH, une amine primaire, secondaire ou tertiaire, CN, CO₂H, CO₂R' dans lequel R' est un alkyle linéaire ou ramifié en C1-C8, ou un cycloalkyle en C3-C6,
   • R6, R7, R9 et R11 représentent des hydrogènes,
   • R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un alkyle en C1 à C5 linéaire ou ramifié, au moins l'un des deux étant un alkyle en C1 à C5 linéaire ou ramifié ;
2. b) soit R12 représente CH(R13)(CH₂) et forme un cycle en C5 avec R5, R13 représentant H ou CH₃,
   • R1, R2, R3 et R4 sont sélectionnés parmi le groupe consistant en un hydrogène, un halogène, un alkyle en C1 à C8 linéaire ou ramifié, un alcène en C2-C8, un alcoxy en C1 à C8 linéaire ou ramifié, un cycloalkyle en C3-C6, un bicycloalkyle en C5-C6, une chaîne polyéther, un perfluoroalkyle en C1-C5, un acyle en C1-C8, -OH, -SH, une amine primaire, secondaire ou tertiaire, -CN, -CO₂H, -CO₂R' dans lequel R' est un alkyle linéaire ou ramifié en C1-C8, et un cycloalkyle en C3-C6 ;
   • R6, R7, R9 et R11 représentent des hydrogènes,
   • R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un alkyle en C1 à C5 linéaire ou ramifié, au moins l'un des deux étant un alkyle en C1 à C5 linéaire ou ramifié,
   à condition qu'au moins un parmi R1 et R13 ne soit pas un hydrogène,
   et leurs sels pharmacologiquement acceptables.

Thus, the present invention relates in particular to compounds of general formula (I)

in which :

1. a) R12 is H, and
   • R1 and R2 represent independently of each other:
     • halogen, linear or branched C1-C8 alkyl, C2-C8 alkene, linear or branched C1-C8 alkoxy, C3-C6 cycloalkyl, C5-C6 bicycloalkyl, polyether chain, perfluoroalkyl C1-C5, a C1-C8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H CO ₂ R 'in which R' is a linear or branched C1-C8 alkyl, or a C3-C6 cycloalkyl, or
   • R1 and R2 together form a C5 ring,
   • R3, R4 and R5 represent independently of each other:
     • a hydrogen, a halogen, a linear or branched C1-C8 alkyl, a C2-C8 alkene, a linear or branched C1-C8 alkoxy, a C3-C6 cycloalkyl, a C5-C6 bicycloalkyl, a polyether chain , a C1-C5 perfluoroalkyl, a C1-C8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H, CO ₂ R 'in which R' is a linear or branched C1-C alkyl; C8, or a C3-C6 cycloalkyl,
   • R6, R7, R9 and R11 represent hydrogen,
   • R8 and R10 are selected from the group consisting of hydrogen and C1-C5 linear or branched alkyl, at least one of which is linear or branched C1-C5 alkyl;
2. b) R 12 is CH (R 13) (CH ₂₎ and forms a C 5 ring with R5, R13 representing H or CH _3,
   • R1, R2, R3 and R4 are selected from the group consisting of hydrogen, halogen, linear or branched C1-C8 alkyl, C2-C8 alkene, linear or branched C1-C8 alkoxy, cycloalkyl, and the like. C3-C6, a C5-C6 bicycloalkyl, a chain polyether, a C1-C5 perfluoroalkyl, a C1-C8 acyl, -OH, -SH, a primary, secondary or tertiary amine, -CN, -CO ₂ H, -CO ₂ R 'in which R' is an alkyl linear or branched C1-C8, and a C3-C6 cycloalkyl;
   • R6, R7, R9 and R11 represent hydrogen,
   • R8 and R10 are selected from the group consisting of hydrogen and C1-C5 linear or branched alkyl, at least one of which is linear or branched C1-C5 alkyl;
   provided that at least one of R1 and R13 is not hydrogen,
   and their pharmacologically acceptable salts.

Carbons carrying R13 when it is different from H, or R6 and R7 when they are different from each other, or R8 if it is different from R9 and R10 if it is different from R11, are asymmetric and each of said carbons can therefore be of absolute configuration (R) or (S), or (R, S).

• « alkyle en C-1 à C8 linéaire ou ramifié » désigne un méthyle, éthyle, n-propyle, n-butyle, n-pentyle, n-héxyle, n-heptyle ou n-octyle et tous leurs isomères, à savoir isopropyle, isobutyle, sec-butyl et tert-butyle, l'isopentane (ou 2-méthylbutyle) ou le néopentane (ou 2,2 diméthylpropyle), le 2,2-diméthylbutane, le 2,3-diméthylbutane, le 2-méthylpentane, le 3-méthylpentane, le 2-méthylhexane, le 3-méthylhexane, le 2,2-diméthylpentane, le 2,3-diméthylpentane, le 2,4-diméthylpentane, le 3,3-diméthylpentane, le 3-éthylpentane, le 2,2,3-triméthylbutane, le 2-méthylheptane, le 3-méthylheptane, le 4-méthylheptane, le 2,2-diméthylhexane, le 2,3-diméthylhexane, le 2,4-diméthylhexane, le 2,5-diméthylhexane, le 3,3-diméthylhexane, le 3,4-diméthylhexane, le 3-ethylhexane, le 2,2,3-triméthylpentane, le 2,2,4-triméthylpentane, le 2,3,3-triméthylpentane, le 2,3,4-triméthylpentane, le 2-méthyl-3-ethylpentane, le 3-méthyl-3-éthylpentane, le tetraméthylbutane.
  Ledit alkyle peut également être substitué, notamment par un alcool, un thiol, un éther, un halogène, un nitrile, une amine primaire, secondaire ou tertiaire;
• « alcène en C2-C8 » désigne un éthylène, propène, butène, pentène, héxène, heptène ou octène et tous leurs isomères.
  Ledit alcène peut également être substitué, notamment par un alcool, un thiol, un éther, un halogène, un nitrile, une amine primaire, secondaire ou tertiaire;
• un « acyle en C1-C8 » désigne un groupe -C(O)-alkyle en C1-C8 dont l'alkyle est tel que ci-dessus défini;
• un « sulfonylalkyle en C1-C8» désigne un groupe S(O)₂O-alkyle dans lequel l'alkyle en C1-C8 est tel que ci-dessus défini;
• un halogène désigne un brome, un chlore, un fluor ou un iode;
• un « alcoxy en C1-C8 linéaire ou ramifié » désigne un O-alkyle, c'est-à-dire un alkyle en C1-C8 linéaire ou ramifié ayant la même définition que ci-dessus, relié par un oxygène à la molécule de formule (I).
  Ledit alcoxy peut également être substitué, notamment par un alcool, un thiol, un éther, un halogène, un nitrile, une amine primaire, secondaire ou tertiaire;
• un « cycloalkyle en C3-C6 » désigne un cyclopropyle, cyclobutyle, cyclopentyle ou cyclohéxyle ;
• un « bicycloalkyle en C5-C6 » désigne deux cycles cycloalkyles en C5 et/ou C6 fusionnés;
  Lesdits cycloalkyles ou bicycloalkyles peuvent également être substitués, notamment par un alcool, un thiol, un éther, un halogène, un nitrile, une amine primaire, secondaire ou tertiaire;
• une chaîne polyéther désigne une chaîne O-(CH₂-CH₂-O)_nCH₂-CH₂-OR", n variant de 0 à 9 et R" représentant un alkyle ou alcène ou cycloalkyle tels que définis ci-dessus ;
• un « perfluoroalkyle » en C1-C5 désigne un alkyle en C1-C5, tel que défini ci-dessus, dont tous les hydrogènes sont totalement substitués par un fluor; par exemple CF₃, C₂F₅, C₃F₇, C₄F₉, C₅F₁₁,
• une amine primaire, secondaire ou tertiaire désigne un groupe -NR_aR_b dans lequel R_a et R_b désignent indépendamment l'un de l'autre H, un alkyle linéaire ou ramifié en C1-C6, un cycloalkyle en C3-C6, un acyle en C1-C6.

Throughout the description the following expressions always have the same meaning:

• "Linear or branched C-1 -C 8 alkyl" means methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl and all their isomers, namely isopropyl, isobutyl, sec-butyl and tert-butyl, isopentane (or 2-methylbutyl) or neopentane (or 2,2-dimethylpropyl), 2,2-dimethylbutane, 2,3-dimethylbutane, 2-methylpentane, 3-methylpentane, 2-methylhexane, 3-methylhexane, 2,2-dimethylpentane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2, 2,3-trimethylbutane, 2-methylheptane, 3-methylheptane, 4-methylheptane, 2,2-dimethylhexane, 2,3-dimethylhexane, 2,4-dimethylhexane, 2,5-dimethylhexane, 3,3-dimethylhexane, 3,4-dimethylhexane, 3-ethylhexane, 2,2,3-trimethylpentane, 2,2,4-trimethylpentane, 2,3,3-trimethylpentane, 2,3, 4-trimethylpentane, 2-methyl-3-ethylpentane, 3-methyl-3-ethylpentane, tetramethylbutan e.
  Said alkyl may also be substituted, in particular with an alcohol, a thiol, an ether, a halogen, a nitrile, a primary, secondary or tertiary amine;
• "C2-C8 alkene" means ethylene, propene, butene, pentene, hexene, heptene or octene and all their isomers.
  Said alkene may also be substituted, in particular with an alcohol, a thiol, an ether, a halogen, a nitrile, a primary, secondary or tertiary amine;
• "C1-C8 acyl" refers to a -C (O) -C1-C8 alkyl group whose alkyl is as defined above;
• "C 1 -C 8 -sulfonylalkyl" means S (O) ₂ O -alkyl in which C 1 -C 8 -alkyl is as defined above;
• halogen means bromine, chlorine, fluorine or iodine;
• "linear or branched C1-C8 alkoxy" means an O-alkyl, that is to say a linear or branched C1-C8 alkyl having the same definition as above, connected by oxygen to the molecule of formula (I).
  Said alkoxy may also be substituted, in particular with an alcohol, a thiol, an ether, a halogen, a nitrile, a primary, secondary or tertiary amine;
• "C3-C6 cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
• "C5-C6 bicycloalkyl" refers to two fused C5 and / or C6 cycloalkyl rings;
  Said cycloalkyls or bicycloalkyls may also be substituted, in particular with an alcohol, a thiol, an ether, a halogen, a nitrile, a primary, secondary or tertiary amine;
• a polyether chain denotes a chain O- (CH ₂ -CH ₂ -O) _n CH ₂ -CH ₂ -OR ", n varying from 0 to 9 and R" representing an alkyl or alkene or cycloalkyl as defined above;
• "C1-C5 perfluoroalkyl" denotes a C1-C5 alkyl, as defined above, all of whose hydrogens are completely substituted by a fluorine; for example CF ₃ , C ₂ F ₅ , C ₃ F ₇ , C ₄ F ₉ , C ₅ F ₁₁ ,
• a primary, secondary or tertiary amine denotes a group -NR _a R _b in which R _a and R _b denote, independently of one another, H, a linear or branched C1-C6 alkyl or a C3-C6 cycloalkyl, C1-C6 acyl.

• n = 0, cycle à 5C :
  

When R12 is -CH (R13) (CH ₂₎ and forms a ring with R5 5C represents CH _2, R 13 representing H or CH _3, the following formula I-1 is obtained:

• n = 0, cycle at 5C:
  

In a preferred embodiment, the compounds have the formula I-1.

The expression "pharmacologically acceptable salts" means that the compounds of formula I, defined above, when they have a radical representing an amine, may exist in the form of ammonium by reaction of an inorganic acid or a organic acid on the amine.

Examples of inorganic acids for obtaining pharmacologically acceptable salts include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, formic acid, acid and the like. monohydrogenocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, perchloric acid, sulfuric acid, monohydrogenosulfuric acid, hydroiodic acid.

Examples of organic acids for obtaining pharmacologically acceptable salts include, but are not limited to, acetic acid, lactic acid, propionic acid, butyric acid, isobutyric acid, acid and the like. palmic acid, maleic acid, glutamic acid, hydroxymaleic acid, malonic acid, benzoic acid, succinic acid, glycolic acid, suberic acid, fumaric acid, acid mandelic acid, phthalic acid, salicylic acid, benzenesulfonic acid, p- toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, hydroxynaphthoic acid.

Amino acid salts, such as arginates and their equivalents are also included as well as salts of organic acids such as glucuronic acid or galacturonic acid and their equivalents (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19 ).

Alkyl halides for obtaining pharmacologically acceptable salts include, but are not limited to, bromide, iodide, fluoride or alkyl chloride wherein said alkyl residue is saturated or unsaturated, linear or branched from 1 to 20 carbon atoms, or an O-cycloalkyl group of 3 to 8 carbon atoms.

When the compounds of formula I according to the invention have a radical representing an acid or an OH, in particular a phenol, they may exist in the form of carboxylate, alkoxide or phenate, for example sodium, potassium, lithium or ammonium by reacting the acid, alcohol or phenol with a base such as, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, etc.

Unexpectedly the inventors have observed that the compounds of the invention by their original pyrroline structure are selective for the imidazoline receptor RI ₁ relative to the α ₂ -adrenergic receptor, the ratio Ki (RAα ₂ ) / Ki (RI ₁ ) ranging from 100 to over 10,000.

The compounds of the invention are also selective for the imidazoline RI ₁ receptor relative to the imidazoline RI ₂ receptor, the ratio Ki (RI ₂ ) / Ki (RI ₁ ) being approximately equal to 1000.

In addition, the compounds of the invention are also selective for the imidazoline RI- ₁ receptor compared with more than fifty other potential targets, the receptors or enzymes, in particular those presented in the table of the invention. figure 3 .

Finally, in order to present the desired therapeutic effect, the compounds of the invention are agonists of the imidazoline RI ₁ receptor. This agonist effect can be measured by any method available to those skilled in the art. In particular, it can be tested by measuring the hypotensive capacity of the compounds.

• R1, R2, R3, R4 et R5 représentent indépendamment les uns des autres :
  • H, un halogène, un alkyle en C1 à C8 linéaire ou ramifié, un alcène en C2-C8, un alcoxy en C1 à C8 linéaire ou ramifié, un cycloalkyle en C3-C6, un bicycloalkyle en C5-C6, une chaîne polyéther, un perfluoroalkyle en C1-C5, un acyle en C1-C8, OH, SH, une amine primaire, secondaire ou tertiaire, CN, CO₂H CO₂R' dans lequel R' est un alkyle linéaire ou ramifié en C1-C8, ou un cycloalkyle en C3-C6,
    R1 et R2 et/ou R2 et R3 et/ou R3 et R4 et/ou R4 et R5 pouvant également former ensemble un cycle en C4-C6,
• R6, R7, R8, R9, R10 et R11 représentent indépendamment les uns des autres:
  • H, un alkyle en C1 à C8 linéaire ou ramifié, un alcène en C2-C8, un cycloalkyle en C3-C6,
• R12 représente H, un alkyle en C1 à C8 linéaire ou ramifié, un alcène en C2-C8, un acyle en C1-C8, un sulfonylalkyle en C1-C8.

In an advantageous embodiment, the present invention relates to compounds as defined above, of general formula (I) in which:

• R1, R2, R3, R4 and R5 represent independently of each other:
  • H, a halogen, a linear or branched C1-C8 alkyl, a C2-C8 alkene, a linear or branched C1-C8 alkoxy, a C3-C6 cycloalkyl, a C5-C6 bicycloalkyl, a polyether chain, a C1-C5 perfluoroalkyl, a C1-C8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H CO ₂ R 'in which R' is a linear or branched C1-C8 alkyl, or a C3-C6 cycloalkyl,
    R1 and R2 and / or R2 and R3 and / or R3 and R4 and / or R4 and R5 may also together form a C4-C6 ring,
• R6, R7, R8, R9, R10 and R11 represent independently of each other:
  • H, linear or branched C1-C8 alkyl, C2-C8 alkene, C3-C6 cycloalkyl,
• R12 represents H, a linear or branched C1-C8 alkyl, a C2-C8 alkene, a C1-C8 acyl, a C1-C8 sulphonylalkyl.

dans laquelle R8 et R10 représentent indépendamment l'un de l'autre H ou un alkyle C1 à C5 linéaire ou ramifié, en particulier CH₃, R3 à R5 sont tels que définis ci-dessus et R12 représente H, un alkyle en C1 à C6 linéaire ou ramifié, un alcène en C2-C8, un acyle en C1-C8, un sulfonylalkyle en C1-C8.In an advantageous embodiment, the present invention relates to compounds as defined above, of general formula (Ia) below:

wherein R8 and R10 independently of one another are H or linear or branched C1 to C5 alkyl, in particular CH ₃ , R3 to R5 are as defined above and R12 is H, C1 to C6 alkyl; C6 linear or branched, a C2-C8 alkene, a C1-C8 acyl, a C1-C8 sulfonylalkyl.

Preferably, R12 is hydrogen, and R8 and R10 are selected from the group consisting of hydrogen and linear or branched C1-C5 alkyl, at least one of which is linear or branched C1-C5 alkyl. More particularly, R8 and R10 are selected from the group consisting of hydrogen and methyl or isobutyl so that one of them is hydrogen and the other is methyl or isobutyl, preferably methyl. In a preferred embodiment, R3 is hydrogen. In an even more preferred embodiment, R3, R4 is R5 are hydrogens.

dans laquelle

• R3 et R12 sont des hydrogènes,
• R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un alkyle en C1 à C5 linéaire ou ramifié, au moins l'un des deux étant un alkyle en C1 à C5 linéaire ou ramifié, et
• R4 et R5 sont sélectionnés indépendamment parmi le groupe consistant en un hydrogène, un halogène, un alkyle en C1 à C3 linéaire ou ramifié, un alcoxy en C1 à C3 linéaire ou ramifié, un perfluoroalkyle en C1-C3, un acyle en C1-C3, OH, SH, une amine primaire, secondaire ou tertiaire, CN, CO₂H et CO₂R' dans lequel R' est un alkyle linéaire ou ramifié en C1-C3, de préférence parmi groupe consistant en un halogène, un alkyle en C1 à C3 linéaire ou ramifié, un alcoxy en C1 à C3 linéaire ou ramifié, un perfluoroalkyle en C1-C3, et un acyle en C1-C3.

In another advantageous embodiment, the present invention relates to compounds as defined above, of the following general formula (Ia):

in which

• R3 and R12 are hydrogens,
• R8 and R10 are selected from the group consisting of hydrogen and C1-C5 linear or branched alkyl, at least one of which is linear or branched C1-C5 alkyl, and
• R4 and R5 are independently selected from the group consisting of hydrogen, halogen, linear or branched C1 to C3 alkyl, linear or branched C1 to C3 alkoxy, C1 to C3 perfluoroalkyl, C1 to C3 acyl. , OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H and CO ₂ R 'in which R' is a linear or branched C1-C3 alkyl, preferably from a group consisting of a halogen, an alkyl, C1 to C3 linear or branched, a linear or branched C1 to C3 alkoxy, a C1-C3 perfluoroalkyl, and a C1-C3 acyl.

Preferably, R4 and R5 are hydrogens.

dans laquelle R8 et R10 représentent indépendamment les uns des autres H ou un alkyle C1 à C5 linéaire ou ramifié, en particulier CH₃, R1 et R2 représentent indépendamment les uns des autres H, CH₃ ou C1, R3 à R5 sont tels que définis ci-dessus et R12 représente H, un alkyle en C1 à C8 linéaire ou ramifié, un alcène en C2-C8, un acyle en C1-C8, un sulfonylalkyle en C1-C8.In another advantageous embodiment, the present invention relates to compounds as defined above, of the following general formula (Ib):

in which R 8 and R 10 independently of one another are H or a linear or branched C1 to C5 alkyl, in particular CH ₃ , R 1 and R 2 are independently of each other H, CH ₃ or C 1, R 3 to R 5 are as defined above and R12 is H, C1-C8 linear or branched alkyl, C2-C8 alkene, C1-C8 acyl, C1-C8 sulfonylalkyl.

Preferably, R12 is hydrogen. Preferably, R8 and R10 are selected from the group consisting of hydrogen and linear or branched C1-C5 alkyl, at least one of which is linear or branched C1-C5 alkyl. More particularly, R8 and R10 are selected from the group consisting of hydrogen and methyl or isobutyl so that one of them is hydrogen and the other is methyl or isobutyl, preferably methyl. Preferably, R1 and R2 are independently of each other CH ₃ or C1. In particular, R 1 is methyl and R 2 is methyl or chloride. In an even more preferred embodiment, R3, R4 is R5 are hydrogens.

dans laquelle

• R12 est un hydrogène,
• R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un alkyle en C1 à C5 linéaire ou ramifié, au moins l'un des deux étant un alkyle en C1 à C5 linéaire ou ramifié,
• R1 et R2 sont sélectionnés indépendamment parmi le groupe consistant en un halogène, un alkyle en C1 à C3 linéaire ou ramifié, un alcoxy en C1 à C3 linéaire ou ramifié, un perfluoroalkyle en C1-C3, et un acyle en C1-C3, et
• R3, R4 et R5 sont sélectionnés indépendamment parmi le groupe consistant en un hydrogène, un halogène, un alkyle en C1 à C3 linéaire ou ramifié, un alcoxy en C1 à C3 linéaire ou ramifié, un perfluoroalkyle en C1-C3, un acyle en C1-C3, OH, SH, une amine primaire, secondaire ou tertiaire, CN, CO₂H et CO₂R' dans lequel R' est un alkyle linéaire ou ramifié en C1-C3, de préférence parmi groupe consistant en un halogène, un alkyle en C1 à C3 linéaire ou ramifié, un alcoxy en C1 à C3 linéaire ou ramifié, un perfluoroalkyle en C1-C3, et un acyle en C1-C3.

In another advantageous embodiment, the present invention relates to compounds as defined above, of the following general formula (Ib):

in which

• R12 is a hydrogen,
• R8 and R10 are selected from the group consisting of hydrogen and C1-C5 linear or branched alkyl, at least one of which is linear or branched C1-C5 alkyl;
• R1 and R2 are independently selected from the group consisting of halogen, linear or branched C1 to C3 alkyl, linear or branched C1 to C3 alkoxy, C1 to C3 perfluoroalkyl, and C1 to C3 acyl, and
• R3, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, linear or branched C1-C3 alkyl, linear or branched C1-C3 alkoxy, C1-C3 perfluoroalkyl, C1-acyl. -C3, OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H and CO ₂ R 'in which R' is a linear or branched C1-C3 alkyl, preferably from a group consisting of a halogen, a linear or branched C1-C3 alkyl, linear or branched C1-C3 alkoxy, C1-C3 perfluoroalkyl, and C1-C3 acyl.

Preferably, R1 and R2 are independently selected from the group consisting of halogen and linear or branched C1 to C3 alkyl. Still more preferred way, R1 and R2 are independently of each other CH ₃ or C1.

Preferably, R3, R4 and R5 are hydrogens.

dans laquelle R3 et R8 sont tels que définis ci-dessus. De préférence, R8 est un alkyle en C1 à C5 linéaire ou ramifié, en particulier un méthyle ou un isobutyle, de préférence un méthyle. De préférence, R3 est un hydrogène.In another advantageous embodiment, the present invention relates to compounds as defined above, of formula (Ia-1) below:

wherein R3 and R8 are as defined above. Preferably, R8 is linear or branched C1-C5 alkyl, in particular methyl or isobutyl, preferably methyl. Preferably, R3 is hydrogen.

dans laquelle R1, R2, R8 et R10 sont tels que définis ci-dessus. De préférence, R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un alkyle en C1 à C5 linéaire ou ramifié, au moins l'un des deux étant un alkyle en C1 à C5 linéaire ou ramifié. Plus particulièrement, R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un méthyle ou isobutyle de manière à ce que l'un d'eux soit un hydrogène et l'autre un méthyle ou isobutyle, de préférence un méthyle. De préférence, R1 et R2 sont sélectionnés parmi le groupe consistant en un halogène, un alkyle en C1 à C8 linéaire ou ramifié, un alcoxy en C1 à C8 linéaire ou ramifié, un perfluoroalkyle en C1-C5, un acyle en C1-C8, OH, SH, une amine primaire, secondaire ou tertiaire, CN, CO₂H, et CO₂R' dans lequel R' est un alkyle linéaire ou ramifié en C1-C8, ou forment ensemble un cycle en C5. Plus particulièrement, R1 et R2 sont sélectionnés parmi le groupe consistant en un halogène, un alkyle en C1 à C3 linéaire ou ramifié, un alcoxy en C1 à C3 linéaire ou ramifié, un perfluoroalkyle en C1-C3, et un acyle en C1-C3, ou forment ensemble un cycle en C5. De préférence, R1 et R2 représentent indépendamment les uns des autres CH₃ ou C1. En particulier, R1 est un méthyle et R2 est un méthyle ou un chlorure.In another advantageous embodiment, the present invention relates to compounds as defined above, of formula (Ib-1) below:

wherein R1, R2, R8 and R10 are as defined above. Preferably, R8 and R10 are selected from the group consisting of hydrogen and linear or branched C1-C5 alkyl, at least one of which is linear or branched C1-C5 alkyl. More particularly, R8 and R10 are selected from the group consisting of hydrogen and methyl or isobutyl so that one of them is hydrogen and the other is methyl or isobutyl, preferably methyl. Preferably, R1 and R2 are selected from the group consisting of halogen, linear or branched C1-C8 alkyl, linear or branched C1-C8 alkoxy, C1-C5 perfluoroalkyl, C1-C8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H, and CO ₂ R 'wherein R' is a linear alkyl or branched to C 1 -C 8, or together form a C 5 ring. More particularly, R 1 and R 2 are selected from the group consisting of halogen, linear or branched C1 to C3 alkyl, linear or branched C1 to C3 alkoxy, C1 to C3 perfluoroalkyl, and C1 to C3 acyl. , or together form a C5 cycle. Preferably, R1 and R2 are independently of each other CH ₃ or C1. In particular, R 1 is methyl and R 2 is methyl or chloride.

In another advantageous embodiment, the present invention relates to compounds as defined above, chosen from one of the following formulas:

Preferably, the compounds are selected from the group consisting of

dans laquelle, R1 à R4 et R6 à R11 et sont tels que définis ci-dessus et R13 représente H ou CH₃.In another advantageous embodiment, the present invention relates to compounds as defined above, of general formula (Ic) below:

wherein, R1 to R4 and R6 to R11 and are as defined above and R13 is H or CH _3.

In a particular embodiment of the compounds of general formula (Ic), R13 represents a methyl.

In a particular embodiment of the compounds of general formula (Ic), R1 is not hydrogen.

In a preferred embodiment of the compounds of general formula (Ic), R13 is methyl and / or R1 is not hydrogen. Thus, when R13 is hydrogen, then R1 is not hydrogen. Similarly, at least one of R1 and R13 is not hydrogen,

R1 is selected from the group consisting of hydrogen, halogen, linear or branched C1-C8 alkyl, C2-C8 alkene, linear or branched C1-C8 alkoxy, C3-C6 cycloalkyl, bicycloalkyl at C5-C6, a polyether chain, a C1-C5 perfluoroalkyl, a C1-C8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H, CO ₂ R 'in which R' is a linear or branched C1-C8 alkyl, and a C3-C6 cycloalkyl, preferably from the group consisting of hydrogen, halogen, linear or branched C1-C8 alkyl, C2-C8 alkene, alkoxy; linear or branched C1 to C8, a polyether chain, a C1-C5 perfluoroalkyl, a C1-C8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H and CO ₂ R 'in which R 'is linear or branched C1-C8 alkyl, even more preferably from the group consisting of hydrogen, halogen, linear C1-C3 alkyl or branched, linear or branched C1-C3 alkoxy, C1-C3 perfluoroalkyl, and C1-C3 acyl. In a preferred embodiment, R1 is hydrogen or linear or branched C1 to C3 alkyl, preferably methyl. Preferably, R2, R3 and R4 are hydrogens.

In a particular embodiment of the compounds of general formula (Ic), among R1, R2, R3 and R4, three of them are hydrogens and the latter is selected from the group consisting of H, halogen, alkyl, C1 to C8 linear or branched, a C2-C8 alkene, a linear or branched C1-C8 alkoxy, a C3-C6 cycloalkyl, a C5-C6 bicycloalkyl, a polyether chain, a C1-C5 perfluoroalkyl, a C1-C8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H CO ₂ R 'in which R' is a linear or branched C1-C8 alkyl, and a C3-C6 cycloalkyl, preferably from the group consisting of H, halogen, linear or branched C1-C8 alkyl, C2-C8 alkene, linear or branched C1-C8 alkoxy, polyether chain, C1-C5 perfluoroalkyl, a C 1 -C 8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H and CO ₂ R 'in which R' is a linear alkyl or branched C1-C8, even more preferably from the group consisting of H, halogen, linear or branched C1-C3 alkyl, linear or branched C1-C3 alkoxy, C1-C3 perfluoroalkyl, and a C1-C3 acyl. In a preferred embodiment, of R 1, R 2, R 3 and R 4, three of them are hydrogen and the last is hydrogen or straight or branched C 1 to C 3 alkyl, preferably hydrogen or methyl. Preferably, R2, R3 and R4 are hydrogens.

In a particular embodiment of the compounds of general formula (Ic), R6, R7, R9 and R11 are hydrogen, and R8 and R10 are independently selected from the group consisting of H, linear or branched C1-C8 alkyl, a C2-C8 alkene, a C3-C6 cycloalkyl, a C1-C5 perfluoroalkyl, preferably from the group consisting of H and a linear or branched C1-C8 alkyl, even more preferably from the group consisting of H and linear or branched C1 to C3 alkyl. Preferably, at least one of R8 and R10 is hydrogen. In a preferred embodiment, R6, R7, R9 and R11 are hydrogen, and R8 and R10 are selected from the group consisting of H and linear or branched C1 to C3 alkyl, preferably from H and methyl, at least one of them being hydrogen.

• R1, R2, R3 et R4 sont sélectionnés parmi le groupe consistant en un hydrogène, un halogène, un alkyle en C1 à C3 linéaire ou ramifié, un alcoxy en C1 à C3 linéaire ou ramifié, un perfluoroalkyle en C1-C3, un acyle en C1-C3, OH, SH, une amine primaire, secondaire ou tertiaire, -CN, -CO₂H, et -CO₂R' dans lequel R' est un alkyle linéaire ou ramifié en C1-C3;
• R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un alkyle en C1 à C5 linéaire ou ramifié, au moins l'un des deux étant un hydrogène,

à condition qu'au moins un parmi R1 et R13 ne soit pas un hydrogène.The present invention relates in particular to compounds as defined above, of general formula (Ic)
in which,

• R1, R2, R3 and R4 are selected from the group consisting of hydrogen, halogen, linear or branched C1 to C3 alkyl, linear or branched C1 to C3 alkoxy, C1 to C3 perfluoroalkyl, acyl to C1-C3, OH, SH, a primary, secondary or tertiary amine, -CN, -CO ₂ H, and -CO ₂ R 'wherein R' is a linear or branched C1-C3 alkyl;
• R8 and R10 are selected from the group consisting of hydrogen and linear or branched C1-C5 alkyl, at least one of which is hydrogen,

provided that at least one of R1 and R13 is not hydrogen.

• R2, R3, R4, R6, R7, R9, R10 et R11 sont des hydrogènes;
• R13 est H et R1 est un halogène et un alkyle en C1 à C3 linéaire ou ramifié; ou
  R13 est un méthyle, et R1 est sélectionné parmi le groupe consistant en un hydrogène, un halogène et un alkyle en C1 à C3 linéaire ou ramifié ; et
• R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un alkyle en C1 à C5 linéaire ou ramifié, au moins l'un des deux étant un hydrogène.

In a particular embodiment of the compounds of general formula (Ic),

• R2, R3, R4, R6, R7, R9, R10 and R11 are hydrogen;
• R13 is H and R1 is halogen and C1-C3 linear or branched alkyl; or
  R13 is methyl, and R1 is selected from the group consisting of hydrogen, halogen, and linear or branched C1 to C3 alkyl; and
• R8 and R10 are selected from the group consisting of hydrogen and linear or branched C1-C5 alkyl, at least one of which is hydrogen.

• R2, R3, R4, R6, R7, R9, R10 et R11 sont des hydrogènes;
• R13 est H et R1 est un méthyle; ou
  R13 est un méthyle, et R1 est sélectionné parmi le groupe consistant en un hydrogène et un méthyle ; et
• R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un méthyle, au moins l'un des deux étant un hydrogène.

In a still more particular embodiment of the compounds of general formula (Ic),

• R2, R3, R4, R6, R7, R9, R10 and R11 are hydrogen;
• R13 is H and R1 is methyl; or
  R13 is methyl, and R1 is selected from the group consisting of hydrogen and methyl; and
• R8 and R10 are selected from the group consisting of hydrogen and methyl, at least one of which is hydrogen.

dans laquelle, R1, R8 et R9 sont tels que définis ci-dessus et R13 représente H ou CH₃.In another advantageous embodiment, the present invention relates to compounds as defined above, of formula (Ic-1) below:

wherein, R1, R8 and R9 are as defined above and R13 is H or CH _3.

Preferably, R9 is hydrogen and at least one of R1, R8 and R13 is not hydrogen. In one embodiment, two of R1, R8 and R13 are not hydrogens.

Preferably, R1 is selected from the group consisting of H, halogen, linear or branched C1-C8 alkyl, C2-C8 alkene, linear or branched C1-C8 alkoxy, polyether chain, perfluoroalkyl, and the like. C1-C5, a C1-C8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO ₂ H, and CO ₂ R 'wherein R' is a linear or branched C1-C8 alkyl of even more preferably from the group consisting of H, halogen, linear or branched C1 to C3 alkyl, linear or branched C1 to C3 alkoxy, C1 to C3 perfluoroalkyl, and C1 to C3 acyl. In particular, R 1 is selected from the group consisting of H, halogen, linear or branched C 1 -C 3 alkyl. In particular, R 1 is H or methyl.

Preferably, R8 is selected from the group consisting of H and linear or branched C1 to C8 alkyl, even more preferably from the group consisting of H and linear or branched C1 to C3 alkyl. In particular, R8 is H or methyl.

• R9 est un hydrogène ;
• R13 est H et R1 est un halogène et un alkyle en C1 à C3 linéaire ou ramifié; ou
  R13 est un méthyle et R1 est sélectionné parmi le groupe consistant en un hydrogène, un halogène et un alkyle en C1 à C3 linéaire ou ramifié ; et
• R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un alkyle en C1 à C5 linéaire ou ramifié, au moins l'un des deux étant un hydrogène.

In a particular embodiment of the compounds of general formula (Ic-1),

• R9 is hydrogen;
• R13 is H and R1 is halogen and C1-C3 linear or branched alkyl; or
  R13 is methyl and R1 is selected from the group consisting of hydrogen, halogen, and linear or branched C1 to C3 alkyl; and
• R8 and R10 are selected from the group consisting of hydrogen and linear or branched C1-C5 alkyl, at least one of which is hydrogen.

• R9 est un hydrogène;
• R13 est H et R1 est un méthyle; ou
  R13 est un méthyle, et R1 est sélectionné parmi le groupe consistant en un hydrogène et un méthyle ; et
• R8 et R10 sont sélectionnés parmi le groupe consistant en un hydrogène et un méthyle, au moins l'un des deux étant un hydrogène.

In a still more particular embodiment of the compounds of general formula (Ic-1),

• R9 is hydrogen;
• R13 is H and R1 is methyl; or
  R13 is methyl, and R1 is selected from the group consisting of hydrogen and methyl; and
• R8 and R10 are selected from the group consisting of hydrogen and methyl, at least one of which is hydrogen.

In another advantageous embodiment, the present invention relates to compounds as defined above, chosen from one of the following formulas:

The compounds according to the invention can be synthesized by methods known to those skilled in the art, described in the literature from commercially available compounds or prepared according to techniques known to those skilled in the art.

According to another aspect, the present invention relates to compounds as defined above, for their use for the prevention and / or treatment of the metabolic syndrome.

The compounds of the invention, which are selective for the RI ₁ receptor, with imidazolines not only make it possible to have compounds devoid of side effects, in particular due to the interaction with the α ₂ A receptor such as sedation, which retain a hypotensive effect but still allow to treat, as monotherapy, all the components of the metabolic syndrome, namely arterial hypertension, hypercholesterolemia, insulin resistance, glucose intolerance and abdominal obesity, thus avoiding the use of an association of 3 to 6 drugs with multiple side effects and additional costs for health insurance systems.

The monotherapy and the absence of side effects such as sedation observed in the animal should allow the use of the compounds of the invention within the framework of the prevention of the metabolic syndrome or of one or more of the components of the syndrome. metabolic rate in patients at risk for one or other of these components.

According to another aspect, the present invention relates to a pharmaceutical composition comprising as active ingredient at least one compound defined above, in association with a pharmaceutically acceptable vehicle.

By pharmaceutically acceptable carrier is meant any substance other than the active ingredient in a drug. Its addition is intended to confer physicochemical and / or biochemical characteristics to promote oral, sublingual, respiratory, rectal, nasal, intestinal, parenteral, intravenous, intraperitoneal, intramuscular, subcutaneous, or d other characteristics of consistency or taste to the final product, preferably avoiding covalent chemical interactions with the active ingredients.

The pharmaceutical compositions of the invention may be in the form of single or sugar-coated tablets, sublingual tablets, capsules, glossettes, capsules, lozenges, injectables, aerosols, nasal drops, suppositories, creams. , ointments or dermal gels.

According to another aspect, the present invention relates to a method for treating the metabolic syndrome by administering to a patient, in particular orally, a pharmaceutical composition comprising as active ingredient at least one compound defined above, in association with a vehicle. pharmaceutically acceptable, at an effective dose.

In an advantageous embodiment, the present invention relates to a pharmaceutical composition as defined above, which can be administered orally.

In an advantageous embodiment, the active principle of the orally administrable pharmaceutical composition defined above is at a dose of from 1 mg / kg to 100 mg / kg in humans.

Below 1 mg / kg, the dose is too low to obtain an activity in the treatment of the metabolic syndrome, beyond 100 mg / kg, there is a risk of occurrence of side effects.

Examples A and 1 to 5 and the Figures 1 to 8 which follow illustrate the invention.

CHEMICAL PART

• CDCl₃: Chloroforme deutérié
• iPrOH: Isopropanol
• Et₂O: Ether diéthylique
• POCl₃: Trichlorure de phosphore
• TEA: Triéthylamine
• TMG: Tétraméthylguanidine

Abbreviations used:

• CDCl ₃ : Deuterated chloroform
• iPrOH: Isopropanol
• And ₂ O: diethyl ether
• POCl ₃ : phosphorus trichloride
• TEA: Triethylamine
• TMG: Tetramethylguanidine

All solvents were purified according to standard procedures prior to use. Thin layer chromatography was carried out on 60F254 silica plate (Merck) and the stains were visualized using a UV lamp. The flash chromatographies were carried out on silica gel SI 60 (40-63 μm) as stationary phase. Melting points (p, f,) were determined in open capillaries with a Gallenkamp apparatus and are uncorrected. NMR spectra were recorded in CDCl ₃ or D ₂ O on a Brucker AV300 spectrometer. The chemical shifts (δ) are expressed in parts per million (ppm), the coupling constants are expressed in Hertz (Hz). The abbreviations used for the multiplicities are: m: unspecified multiplet, s: singlet, d: doublet, t: triplet, q: quadruplet, qn: quintuplet, hex: hexuplet, h: heptuplet. The elementary analyzes were carried out at the microanalysis department of Louis Pasteur University, Strasbourg, France. The analytical results obtained for C, H and N are indicated with ± 0.4% of the calculated theoretical values. All target compounds were tested as hydrochloride. The hydrochlorides were prepared by addition of a basic ethanolic solution (1 eq). The hydrochlorides were recrystallized from iPrOH-Et ₂ O.

EXAMPLE A General Procedure for the Preparation of Aminopyrrolines 1 - 27 of the Invention

The compounds are synthesized by reaction of the appropriate lactam with the corresponding aniline in the presence of POCl ₃ :

A.1: General procedure for L lactam synthesis ( 28 - 33 ):

A.1.1: Preparation of nitroesters 35 - 38 : general procedure

The α, β-unsaturated ester ( 39 - 41 ) (1 eq) was added to the excess nitroalkane (5 eq) under an argon atmosphere. A catalytic amount of tetramethylguanidine (0.1 eq) was added to the mixture which was stirred for 12 h at room temperature. The excess nitroalkane was distilled under reduced pressure and the residue was treated with 2N HCl.

The mixture was extracted with Et ₂ O. The organic phase was washed with water, then with brine and finally dried over anhydrous Na ₂ SO ₄ before the solvent was evaporated. The product was distilled under reduced pressure to give pure nitroester.

Methyl -4-nitro-butyrate ( 34 ) commercial product

Methyl 3-methyl-4-nitro-butyrate ( 35 ). Yield 85%, colorless oil, bp 69-70 ° C (3 mmHg); ¹ H NMR (CDCl ₃ ) δ 4.47 (dd, 1H, 1/2-CH ₂ , J = 6.3, J = 12.6); 4.34 (dd, 1H, 1/2-CH ₂ , J = 6.3, J = 12.6); 3.69 (s, 3H, CH ₃ ); 2.78 (qd, 1H, CH, J = 6.8, J = 13.5); 2.46 (dd, 1H, 1/2-CH ₂ , J = 6.7, J = 16.2); 2.35 (dd, 1H, 1/2-CH ₂ , J = 6.8, J = 16.2); 1.09 (d, 3H, CH ₃ , J = 6.8).

Methyl 4-methyl-4-nitro-pentanoate ( 36 ). Yield 55%, colorless oil, bp 71-72 ° C (2.5 mmHg); ¹ H NMR (CDCl ₃₎ δ 3.68 (s, 3H, OCH _3); 2.37-2.23 (m, 4H, 2xCH ₂ ); 1.59 (s, 6H, 2xCH ₃ ).

Methyl 3,3-Dimethyl-4-nitro-butyrate ( 37 ) . Yield 48%, colorless oil, bp 70-71 ° C (1.5 mmHg); ¹ H NMR (CDCl ₃₎ δ 4.52 (s, 2H, CH _2); 3.67 (s, 3H, CH ₃ ); 2.45 (s, 2H, CH ₂ ); 1.15 (s, 6H, 2xCH ₃ ).

Methyl 4- (2-methyl-propyl) -4-nitro-pentanoate ( 38 ) , yield 45%, oil
¹ H NMR (CDCl ₃ ) δ 3.75 (m, 1H); 3.69 (s, 3H); 2.39-2.24 (m, 4H); 1.85 (m, 2H); 1.60 (m, 1H); 0.95 (d, J = 7 Hz, 6H).

A.1.2 Preparation of lactams L 30 - 33 :

The nitroester 34-38 (100 mmol) was dissolved in 250 ml of glacial acetic acid and 500 mg of Pd-C 10% was added. The mixture was hydrogenated at room temperature and atmospheric pressure for 12h. The mixture was filtered and the solvent evaporated. The product was then dissolved in 100 ml absolute ethanol and basified with triethylamine (TEA). The mixture was refluxed for 12h. The solvents were evaporated under reduced pressure; the residue was diluted in Et ₂ O and 1N HCl was added. The aqueous phase was extracted twice with Et2O.

The organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated. The product was purified by distillation under reduced pressure to give the lactams 30-33.

Pyrrolidin-2-one ( 28 ) commercial product

3-Methyl-pyrrolidin-2-one ( 29 ) commercial product

4-Methyl-pyrrolidin-2-one ( 30 ) . Yield 83%, colorless oil, (crystallizes afterwards), bp 103 ° C (6 mmHg); ¹ H NMR (CDCl ₃₎ δ 6.75 (br s, 1H, NH); 3.46 (dd, 1H, 1/2-CH ₂ , J = 7.6, J = 9.3); 2.93 (dd, 1H, 1/2-CH ₂ , J = 6.0, J = 9.5); 2.53-2.44 (m, 1H, CH); 2.46 (dd, 1H, 1/2-CH ₂ , J = 6.9, J = 16.3); 1.94 (dd, 1H, 1/2-CH ₂ , J = 7.0, J = 16.2); 1.10 (d, 3H, CH ₃ , J = 6.9).

5,5-Dimethyl-pyrrolidin-2-one ( 31 ) . Yield 61%, colorless oil, (crystallizes afterwards), bp 85-88 ° C (2 mmHg); ¹ H NMR (CDCl ₃ δ 6.52 (br s, 1H, NH); 2.42 (t, 2H, CH _2, J = 8.0), 1.92 (t, 2H, CH _2, J = 8.0), 1.28 (s, 6H, 2xCH ₃ ).

4,4-Dimethyl-pyrrolidin-2-one ( 32 ) . Yield 73%, colorless oil, (crystallizes afterwards), bp 94-95 ° C (2 mmHg); ¹ H NMR (CDCl ₃₎ δ 6.68 (br s, 1H, NH); 3.06 (s, 2H, CH ₂ ); 2.11 (s, 2H, CH ₂ ); 1.16 (s, 6H, 2xCH ₃ ).

5- (2-methyl-propyl) -pyrrolidin-2-one ( 33 ) , yield 67%, viscous oil.
¹ H NMR (CDCl ₃ δ 6.68 (m, 1H); 3.75 to 3.70 (m, 1H); 2.38 to 2.19 (m, 3H); 1.72 to 1 , 60 (m, 2H); 1.68 (m, 1H), 1.52-1.42 (m, 1H); 1.36-1.26 (m, 1H) 0.93 (d, J); = 8 Hz, 6 H).

A.1.3 Preparation of indian derivatives 42-44

a) Indan-4-ylamine and indan-5-ylamine

Nitroindane (commercial mixture of isomers 4 and 5) was hydrogenated in methanol with 10% Pd / C at room temperature for 12h. The two isomers of indanylamine were separated by flash chromatography (AcOEt-hexane, 3-7) to provide indan-4-ylamine (brown oil which crystallizes) with 53% yield and indan-5-ylamine ( brown oil that crystallizes) with 40% yield.

¹ H NMR (CDCl ₃ ) (Indan-4-ylamine) δ 7.69 (d, 1H, H f, J = 8.1); 7.18 (t, 1H, H, J = 8.1); 7.04 (d, 1H, Har, J = 8.0); 6.88 (brs, 2H, NH ₂ ); 2.93 (t, 2H, CH ₂ , J = 7.5); 2.84 (t, 2H, CH ₂ , J = 7.4); 2.11 (qn, 2H, CH ₂ , J = 7.5)

b) Preparation of the indane derivative 42

Indan-4-ylamine was dissolved in pure acetic anhydride at 0 ° C. The resulting precipitate which appears rapidly was filtered and washed with water. The product was recovered in 90% yield (white-gray solid) and is pure enough to be used for the next step without further purification.

¹ H NMR (CDCl ₃₎ δ 7.73 (d, 1H, Har, J = 8.1); 7.15 (t, 1H, H, J = 8.1); 7.02 (d, 1H, H, J = 8.0); 6.96 (brs, 1H, NH); 2.95 (t, 2H, CH ₂ , J = 7.5); 2.81 (t, 2H, CH _2, J = 7.4); 2.18 (s, 3H, CH ₃ ); 2.10 (qn, 2H, CH ₂ , J = 7.5).

The product obtained above (1 g) was dissolved in 20 ml of glacial acetic acid and a solution of chlorine in freshly prepared glacial acetic acid was added (1 eq). After 20 min, 30 ml of water was added and the mixture was stirred for 10 min. The precipitate which appears was filtered and washed with saturated aqueous sodium carbonate solution, with 20% Na ₂ S ₂ O ₅ and with water. The product was dried in a desiccator to yield 7-chloro-4-acetamidoindan compound in 96% yield as a white solid.

¹ H NMR (CDCl ₃₎ δ 7.72 (d, 1H, Har, J = 8.6); 7.12 (d, 1H, Har J = 8.6); 7.0 (brs, 1H, NH); 2.99 (t, 2H, CH ₂ , J = 7.5); 2.87 (t, 2H, CH ₂ , J = 7.5); 2.16 (s, 3H, CH ₃ ); 2.11 (qn, 2H, CH ₂ , J = 7.5).

7-Chloro-4-acetamidoindane (1g) was resuspended in 50 ml of 4N HCl and the mixture was refluxed for 2h. After cooling, the mixture was washed with AcOEt, basified with NaOH pellets until the pH was slightly basic. The mixture was extracted with Et ₂ O. The organic phase was washed with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated and aniline 42 was obtained in almost quantitative yield.

¹ H NMR (CDCl ₃ ) δ 7.01 (d, 1H, Har, J = 8.4); 6.47 (d, 1H, H, J = 8.4); 3.55 (brs, 2H, NH ₂ ); 2.94 (t, 2H, CH ₂ , J = 7.5); 2.83 (t, 2H, CH ₂ , J = 7.5); 2.13 (qn, 2H, CH ₂ , J = 7.4).

c) Preparation of the indane derivative 43

The procedure is the same as for aniline 42 except that bromine is used in place of chlorine.

The 7-bromo-4-acetamidoindane compound was obtained in 92% yield as a white solid.

¹ H NMR (CDCl ₃ ) δ 7.65 (d, 1H, Har, J = 8.6); 7.28 (d, 1H, H, J = 8.6); 6.89 (brs, 1H, NH); 2.97 (t, 2H, CH ₂ , J = 7.6); 2.90 (t, 2H, CH ₂ , J = 7.5); 2.18 (s, 3H, CH ₃ ); 2.13 (qn, 2H, CH ₂ , J = 7.6). The 7-bromo-4-acetamidoindane compound was dissolved in dioxane (10 ml) and the mixture was degassed and placed under an argon atmosphere. Pd (PPh ₃ ) ₄ (10 mol%) and 5 ml degassed Na ₂ CO ₃ 2 N were added. Trimethylboroxine (1.5 eq) was then added to the mixture by syringe and refluxed for 10h. After cooling, the reaction mixture was diluted with 5 ml of water and filtered. The mixture was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The product was purified by flash chromatography (AcOEt-heaxane, 3-7) to yield the 7-methyl-4-acetamidoindane compound in 80% yield as a white solid.

¹ H NMR (CDCl ₃₎ δ 7.57 (d, 1H, Har, J = 8.2); 6.96 (d, 1H, H, J = 8); 6.89 (brs, 1H, NH); 2.86 (t, 2H, CH ₂ , J = 7.4); 2.82 (t, 2H, CH ₂ , J = 7.4); 2.22 (s, 3H, CH ₃ (ar)); 2.17 (s, 3H, CH _3); 2.10 (qn, 2H, CH ₂ , J = 7.5).

7-methyl-4-acetamidoindane was hydrolyzed in the same manner as 7-chloro-4-acetamidoindane above. Compound 43 was obtained as a brown oil in 95% yield.

¹ H NMR (CDCl ₃ ) δ 6.81 (d, 1H, Har, J = 7.7); 6.46 (d, 1H, H, J = 7.8); 3.44 (br s, 2H, NH _2); 2.84 (t, 2H, CH ₂ , J = 7.5); 2.76 (t, 2H, CH ₂ , J = 7.4); 2.18 (s, 3H, CH ₃ (ar)); 2.12 (qn, 2H, CH ₂ , J = 7.5).

d) Preparation of the derivative 44

The protocol used is the same as for derivative 42 but starting from indan-5-ylamine.

¹ H NMR (CDCl ₃ ) δ 7.11 (s, 1H, Har); 6.72 (s, 1H, Har); 3.92 (brs, 2H, NH ₂ ); 2.81 (t, 4H, 2 × CH ₂ , J = 7.5); 2.03 (qn, 2H, CH 2, J = 7.4).

A.1.4 Preparation of aminopyrrolines 1 - 27

A solution of the appropriate lactam 28 - 33 (5 mmol) and the selected aniline derivative was prepared in dichloroethane (10 ml) under an argon atmosphere. POCl ₃ (1 eq) was added dropwise to the mixture, which was then heated at 60 ° C for 6h. The mixture was cooled and hydrolysed with 5 ml of a saturated aqueous solution of Na ₂ CO ₃ . The aqueous phase was extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The product was purified by flash chromatography (3% TEA in AcOEt) to yield one of the aminopyrrolines 1 - 27 .

The products obtained are characterized below by their NMR spectrum.

Hydrochloride (3-Chloro-2-methyl-phenyl) - (4-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (1).

¹ H NMR (D ₂ O) δ 7.45 (d, 1H, H f, J = 7.9); 7.25 (d, 1H, H, J = 7.9); 7.20 (t, 1H, H, J = 7.8); 3.73 to 3.68 (m, 1H, 1/2 CH _2); 3.22-3.16 (m, 2H, 1/2 CH ₂ + CH); 2.77-2.71 (m, 2H, CH ₂ ); 2.22 (s, 3H, CH ₃ ); 1.10 (d, 3H, CH ₃ , J = 6.5). ¹³ C NMR (D ₂ O) δ 169.1; 135.5; 133.4; 132.3; 130.1; 128.1; 125.3; 54.2; 37.9; 29.5; 18.1; 14.2. Anal. (C ₁₂ H ₁₅ ClN ₂ , HCl) C, H, N.

Hydrochloride (3-Chloro-2-methyl-phenyl) - (5- (2-methylpropyl) -4,5-dihydro-3 H -pyrrol-2-yl) -amine (2).

¹ H-NMR (400 MHz, MeOH-d4) δ 7.54 (d, 1H, J = 8Hz), 7.36 (m, 2H), 4.12 (m, 1H), 3, 18 (m, 2H), 2.36 (s, 3H), 1.95 (s, 1H), 1.66 (m, 2H), 1.46 (m, 1H), 0, 95 (d, 6H, J = 8 Hz). ¹³ C-NMR δ (100 MHz, MeOH-d4) δ 131.2, 129.4, 126.5, 61.6, 61.4, 31.5, 31.4, 27.9, 27.8, 26.2, 23.6, 23.5, 22.6, 22.4, 15.2
MS-ESI (m / z): [M + H] ⁺ calc for C ₁₅ H ₂₂ ClN ₂ : 265. Found: 265

Hydrochloride (2,6-Dimethyl-phenyl) - (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (3). (not included in the invention)

¹ H NMR (D ₂ O) δ 7.24 (d, 1H, H f, J = 7.6); 7.17 (t, 1H, H, J = 7.7); 7.06 (d, 1H, H, J = 7.6); 4.02 (h, 1H, CH, J = 6.4); 3.09-2.97 (m, 2H, CH ₂ ); 2.37-2.31 (m, 1H, 1/2 CH ₂ ); 2.24 (s, 3H, CH ₃ ); 2.08 (s, 3H, CH ₃ ); 1.86-1.75 (m, 1H, 1/2 CH ₂ ); 1.13 (d, 3H, CH ₃ , J = 6.4). ¹³ C NMR (D ₂ O) δ 168.2; 139.2; 133.5; 133.1; 131.2; 126.6; 124.0; 56.2; 43.8; 37.0; 28.6; 24.9; 17.2. Anal. (C ₁₃ H ₁₈ N ₂ , HCl) C, H, N.

Hydrochloride (3-Chloro-2-methyl-phenyl) - (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (4).

¹ H NMR (CDCl ₃ ) δ 7.41 (d, 1H, H, J = 7.8); 7.23 (d, 1H, Hr, J = 7.9); 7.18 (t, 1H, H, J = 7.8); 4.02 (h, 1H, CH, J = 6.4); 3.11-3.05 (m, 2H, CH ₂ ); 2.38 - 2.30 (m, 1H, 1/2 CH ₂ ); 2.25 (s, 3H, CH ₃ ); 2.11 (s, 3H, CH ₃ ); 1.88-1.78 (m, 1H, 1/2 CH ₂ ); 1.13 (d, 3H, CH ₃ , J = 6.4). ¹³ C NMR (D ₂ O) δ 168.7; 139.5; 133.4; 132.8; 130.5; 126.8; 123.7; 56.2; 32.3; 30.5; 29.7; 24.9; 20.2. Anal. (C ₁₂ H ₁₅ ClN ₂ , HCl) C, H, N.

Hydrochloride Indan-4-yl- (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (5).

¹ H NMR (D ₂ O δ 7.28 (d, 1H, Har, J = 7.5), 7.21 (t, 1H, Har, J = 7.6), 7.02 (d, 1H, Har, J = 7.6), 4.07 (h, 1H, CH, J = 6.4), 3.04-2.88 (m, 2H, CH ₂ ), 2.88 (t, 2H, CH ₂ , J = 7.5) 2.74 (t, 2H, CH ₂ , J = 7.4) 2.37 (m, 1H, 1/2 CH ₂ ) 2.00 (qn, 2H) , CH _2, J = 7.3); 1.83 to 1.75 (m, 1H, 1/2 CH _2); 1.17 (d, 3H, CH _3, J = 6.4) ¹³ C. NMR (D ₂ O) δ 168.0, 147.6, 140.3, 130.7, 127.9, 125.0, 122.6, 56.8, 32.6, 30.1, 29.9 28.2; 24.8; 19.9 Anal. (C ₁₄ H ₁₈ N ₂ , HCl) C, H, N.

Hydrochloride (2,3-Dimethyl-phenyl) - (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (6).

¹ H NMR (D ₂ O) δ 7.24 (d, 1H, Har, J = 7.6); 7.17 (t, 1H, Har, J = 7.7); 7.06 (d, 1H, Har, J = 7.6); 4.02 (h, 1H, CH, J = 6.4); 3.09-3.01 (m, 2H, CH ₂ ); 2.39-2.29 (m, 1H, 1/2 CH ₂ ); 2.24 (s, 3H, CH ₃ ); 2.08 (s, 3H, CH ₃ ); 1.85-1.78 (m, 1H, 1/2 CH ₂ ); 1.13 (d, 3H, CH ₃ , J = 6.4). ¹³ C NMR (D ₂ O) δ 168.2; 139.2; 133.5; 133.1; 131.2; 126.6; 124.0; 56.2; 43.8; 37.0; 28.6; 24.9; 17.2. Anal. (C ₁₃ H ₁₈ N ₂ .HCl) C, H, N.

Hydrochloride Indan-4-yl- (4-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (7).

¹ H NMR (D ₂ O) δ 7.28 (d, 1H, Har, J = 7.5); 7.21 (t, 1H, H, J = 7.6); 7.03 (d, 1H, H, J = 7.5); 3.70 (dd, 1H, 1/2 CH ₂ , J = 10.8, J = 7.8); 3.19 (dd, 1H, 1/2 CH ₂ , J = 11, J = 6); 3.17-3.11 (m, 1H, 1/2 CH ₂ ); 2.89 (t, 2H, CH ₂ , J = 7.4); 2.74 (t, 2H, CH _2, J = 7.4); 2.68-2.61 (m, 2H, CH + 1/2 CH ₂ ); 2.01 (qn, 2H, CH ₂ , J = 7.5); 1.10 (d, 3H, CH ₃ , J = 7). ¹³ C NMR (D ₂ O) δ 168.3; 147.6; 140.2; 130.5; 127.9; 124.9; 122.5; 54.1; 37.8; 32.6; 29.9; 29.5; 24.7; 17.6. Anal. (C ₁₄ H ₁₈ N ₂ , HCl) C, H, N

Hydrochloride (7-Chloro-indan-4-yl) - (4-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (8).

¹ H NMR (D ₂ O) δ 7.22 (d, 1H, Har, J = 8.3); 7.01 (d, 1H, H, J = 8.4); 3.70 (dd, 1H, 1/2 CH ₂ , J = 10.9, J = 7.7); 3.20 (dd, 1H, 1/2 CH ₂ , J = 10.9, J = 7.2); 3.15-3.09 (m, 1H, 1/2 CH ₂ ); 2.93 (t, 2H, CH _2, J = 7.6); 2.82 (t, 2H, CH ₂ , J = 7.5); 2.69-2.61 (m, 2H, CH + 1/2 CH ₂ ); 2.04 (qn, 2H, CH ₂ , J = 7.6); 1.08 (d, 3H, CH ₃ , J = 6.8). ¹³ C NMR (D ₂ O) δ 168.5; 145.2; 142.4; 130.4; 129.1; 127.8; 124.5; 54.2; 37.9; 32.2; 30.9; 29.5; 23.8; 17.7. Anal. (C ₁₄ H ₁₇ ClN ₂ , HCl) C, H, N.

Hydrochloride (7-Methyl-indan-4-yl) - (4-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (9).

¹ H NMR (D ₂ O) δ 7.06 (d, 1H, Har, J = 8); 6.95 (d, 1H, H, J = 8); 3.7 (dd, 1H, 1/2 CH ₂ , J = 10.8, J = 7.7); 3.21-3.09 (m, 2H, 1/2 CH ₂ + CH); 2.82 (t, 2H, CH 2, J = 7.5); 2.75 (t, 2H, CH ₂ , J = 7.5); 2.70-2.64 (m, 2H, CH ₂ ); 2.19 (s, 3H, CH ₃ ); 2.01 (qn, 2H, CH ₂ , J = 7.5); 1.09 (d, 3H, CH ₃ , J = 6.7). ¹³ C NMR (D ₂ O) δ 168.4; 145.9; 139.8; 135.2; 132.4; 128.5; 128.1; 122.8; 54.0; 37.8; 31.3; 30.1; 29.6; 24.2; 18.1; 17.7. Anal. (C ₁₅ H ₂₀ N ₂ , HCl) C, H, N.

1- (3,4-Dihydro- 2H- pyrrol-5-yl) -2-methylindoline hydrochloride (10) .

¹ H-NMR (400 MHz, MeOH-d4) δ 7.44-7.29 (m, 4H); 4.74 (m, 1H); 3.86 (m, 2H); 6.62-3.56 (m, 2H); 3.29-3.23 (1H); 2.88-2.84 (m, 1H); 2.41-2.32 (m, 2H); 1.35 (d, 3H, J = 5Hz). C-NMR δ (100 MHz, MeOH-d4 δ 116.7, 140.5, 134.5, 129.3, 128.0, 127.9, 117.0, 61.8;
37.0; 33.1; 22.1; 19.3.
MS-ESI (m / z): [M + H] ⁺ calc. for C ₁₃ H ₁₇ N ₂ : 201. Found: 201

7-methyl-1- (3-methyl-3,4-dihydro- 2H- pyrrol-5-yl) indoline hydrochloride (11).

¹ H-NMR (400 MHz, MeOH-d4) δ 7.28-7.20 (m, 3H); 4.228-4.24 (m, 2H); 3.98-3.93 (m, 1H); 3.46-3.39 (m, 2H); 3.23-3.20 (m, 2H); 2.95-84 (m, 2H); 2.29 (s, 3H); 1.26 (d, 3H, J = 8 Hz). ¹³ C-NMR δ (100 MHz, MeOH-d4) δ 168.4; 140.1; 137.8; 131.9; 129.5; 128.8; 124.3; 57.0, 56.2; 54.9; 41.2; 31.6; 31.0; 19.4; 18.7.
MS-ESI (m / z): [M + H] ⁺ calc. for C ₁₃ H ₁₉ N ₂ : 215. Found: 215.

2-methyl-1- (3-methyl-3,4-dihydro- 2H- pyrrol-5-yl) indoline hydrochloride (mixture of diastereoisomers) (12).

Oil, ¹ H-NMR (400 MHz, acetone-d6) δ 7.43-7.17 (m, 4H); 5.30-5.28 (m, 1H); 3.96-3.85 (m, 2H); 3.53-327 (m, 3H); 2.91-2.74 (m, 3H); 1.32-1.04 (m, 6H).

¹³ C-NMR δ (100 MHz, acetone-d6) δ 164.9 (164.4); 140.7; 134.2; 128.7; 127.4; 116.7 (116.6); 61.2 (61.1); 40.6 (40.4); 31.7; 30.4); 25.7; 19.9 (19.8); 18.0
MS-ESI (m / z): [M + H] ⁺ calc for C ₁₃ H ₁₉ N ₂ : 215. Found: 215.

Hydrochloride (2-Chlorophenyl) - (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (13). (not included in the invention)

mp 173-4 ° C. ¹ H NMR (D ₂ O) δ 7.67 (m, 1H, H ar); 7.50-7.53 (m, 3H, Hr); 4.21 (m, 1H, CH); 3.18 (m, 2H, CH ₂ ); 2.51 (m, 1H, 1/2 CH ₂ ); 1.94 (m, 1H, 1/2 CH ₂ ); 1.30 (d, 3H, CH ₃ ). ¹³ C NMR (D ₂ O) δ 168.1; 132.5; 131.4; 131.3; 131.0; 129.3; 128.6; 57.9; 30.9; 28.8; 20.5. Anal. (C ₁₁ H ₁₃ ClN ₂ , HCl) C, H, N.

Hydrochloride (2-Fluoro-5-methyl-phenyl) - (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (14). (not included in the invention

¹ H NMR (D ₂ O) δ 7.20 to 7.09 (m, 3H, Har); 4.11 (hex, 1H, CH, J = 6.8); 3.09-2.98 (m, 2H, CH ₂ ); 2.42-2-37 (m, 1H, 1/2 CH ₂ ); 2.25 (s, 3H, CH ₃ ); 1.85-1.73 (m, 1H, 1/2 CH ₂ ); 1.08 (d, 3H, CH ₃ , J = 6.5). ¹³ C NMR (D ₂ O) δ 168.4; 154.3 (d, J ¹ _CF = 244.5); 135.7; 130.9; 126.9; 121.6 (d, J _CF ² = 13.2); 116.4 (d, J ² _CF = 19.5); 57.2; 30.5; 28.1; 21.3; 19.7. ¹⁹ F NMR (D ₂ O) δ -128.3. Anal. (C ₁₂ H ₁₅ FN ₂ , HCl) C, H, N.

Hydrochloride (2-Chloro-5-methyl-phenyl) - (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (15). (not included in the invention

¹ H NMR (D ₂ O) δ 7.38 (dd, 1H, Har, J = 3.1, J = 7.8); 7.18 (d, 1H, 1H, J = 2.9); 7.16 (dd, 1H, Har, J = 3.0, J = 7.7); 4.09-3.96 (m, 1H, CH); 3.07-2.94 (m, 2H, CH ₂ ); 2.41-2.33 (m, 1H, 1/2 CH ₂ ); 2.24 (s, 3H, CH ₃ ); 1.82-1.72 (m, 1H, 1/2 CH ₂ ); 1.16 (d, 3H, CH ₃ , J = 6.3). ¹³ C NMR (D ₂ O) δ 168.5; 139.4; 131.2, 130.2; 128.0; 126.8; 124.4; 57.1; 30.2; 28.1; 19.8; 19.7. Anal. (C ₁₂ H ₁₅ ClN ₂ , HCl) C, H, N

Hydrochloride (4-Fluoro-2-methyl-phenyl) - (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (16). (not included in the invention

¹ H NMR (D ₂ O) δ 7.22 (dd, 1H, Har, J = 5.4, J = 8.7); 7.09 (dd, 1H, H, J = 2.9, J = 8.7); 7.0 (dt, 1H, H, J = 2.9, J = 8.8); 4.14 (hex, 1H, CH, J = 6.7); 3.11-3.03 (m, 2H, CH ₂ ); 2.45-2.97 (m, 1H, 1/2 CH ₂ ); 2.17 (s, 3H, CH ₃ ); 1.81-1.74 (m, 1H, 1/2 CH ₂ ); 1.11 (d, 3H, CH ₃ , J = 6.4). ¹³ C NMR (D ₂ O) δ 169.8; 161.9 (d, J ¹ _CF = 248.8); 137.8 (d, J ³ _CF = 9.2); 129.3 (d, J ⁴ _CF = 2.8); 128.3 (d, J ³ _CF = 9.6); 117.5 (d, J ² _CF = 22.7); 114.2 (d, J ² _CF = 23.0); 55.6; 31.5; 28.8; 19.7; 19.5. ¹⁹ F NMR (D ₂ O) δ -113.4. Anal. (C ₁₂ H ₁₅ FN ₂ , HCl) C, H, N.

Hydrochloride (5,6,7,8-tetrahydro-naphthalen-1-yl) - (5-Methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (17). (not included in the invention

¹ H NMR (D ₂ O) δ 7.17 (d, 2H, Har, J = 7); 7.03 (t, 1H, Har, J = 7.1); 4.06-4.00 (m, 1H, CH); 3.04-2.97 (m, 2H, CH ₂ ); 2.72 (t, 2H, CH ₂ , J = 5.7); 2.51 (t, 2H, CH ₂ , J = 5.9); 2.40-2.32 (m, 1H, 1/2 CH ₂ ); 1.81-1.61 (m, 5H, 1/2 CH ₂ + 2xCH ₂ ); 1.15 (d, 3H, CH _3, J = 6.4). ¹³ C NMR (D ₂ O) δ 168.6; 140.1; 133.9; 133.0; 130.2; 126.6; 123.6; 56.6; 29.9; 28.9; 28.2; 24.1; 22.1; 22.0; 19.8. Anal. (C ₁₅ H ₂₀ N ₂ .HCl) C, H, N.

Hydrochloride Indan-5-yl- (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (18). (not included in the invention

¹ H NMR (D ₂ O) δ 7.26 (d, 1H, Har, J = 8.0); 7.08 (d, 1H, 1H, J = 1.5); 6.96 (dd, 1H, H, J = 1.9, J = 7.9); 4.03 (h, 1H, CH, J = 6.6); 2.99-2.92 (m, 2H, CH ₂ ); 2.80 (t, 4H, 2xCH ₂ , J = 7.5); 2.35-2.29 (m, 1H, 1/2 CH ₂ ); 1.97 (qn, 2H, CH ₂ , J = 7.5); 1.79-1.71 (m, 1H, 1/2 CH ₂ ); 1.16 (d, 3H, CH ₃ , J = 6.4). ¹³ C NMR (D ₂ O) δ 167.7; 145.7; 145.1; 132.7; 125.5; 121.9; 120.1; 56.9; 32.3; 32.0; 30.4; 28.0; 25.3; 19.8. Anal. (C ₁₄ H ₁₈ N ₂ , HCl) C, H, N.

Hydrochloride (6-Chloro-indan-5-yl) - (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (19). (not included in the invention

¹ H NMR (D ₂ O) δ 7.18 (s, 1H, Har); 6.91 (s, 1H, Hr); 4.07 (h, 1H, CH, J = 6.6); 2.97-2.90 (m, 2H, CH ₂ ); 2.81 (t, 4H, 2xCH ₂ , J = 7.5); 2.36-2.28 (m, 1H, 1/2 CH ₂ ); 1.97 (qn, 2H, CH ₂ , J = 7.5); 1.79-1.71 (m, 1H, 1/2 CH ₂ ); 1.63 (d, 3H, CH ₃ , J = 6.4). ¹³ C NMR (D ₂ O) δ 168.5; 145.3; 145.9; 133.4; 127.5; 122.7; 121.6; 57.2; 32.2; 31.8; 30.6; 27.9; 25.5; 21.1. Anal. (C ₁₄ H ₁₇ ClN ₂ , HCl) C, H, N.

Hydrochloride (7-Chloro-indan-4-yl) - (5-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (20).

¹ H NMR (D ₂ O) δ 7.22 (d, 1H, Har, J = 8.3); 7.01 (d, 1H, H, J = 8.4); 4.05 (h, 1H, CH, J = 6.4); 3.05-2.99 (m, 2H, CH ₂ ); 2.93 (t, 2H, CH _2, J = 7.6); 2.81 (t, 2H, CH ₂ , J = 7.5); 2.40-2.32 (m, 1H, 1/2 CH ₂ ); 2.03 (qn, 2H, CH ₂ , J = 7.6); 1.82-1.77 (m, 1H, 1/2 CH ₂ ); 1.17 (d, 3H, CH ₃ , J = 6.4). ¹³ C NMR (D ₂ O) δ 168.4; 145.1; 142.5; 130.5; 129.2; 127.8; 124.4; 56.8; 32.6; 30.1; 29.9; 28.2; 24.8; 19.9. Anal. (C ₁₄ H ₁₈ ClN ₂ , HCl) C, H, N.

Hydrochloride (2,3-Dimethyl-phenyl) - (4-methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (21) .

¹ H NMR (D ₂ O) δ 7.21 (d, 1H, Har, J = 7.7); 7.16 (t, 1H, H, J = 7.7); 7.03 (d, 1H, H, J = 7.6); 3.71-3.65 (m, 1H, 1/2 CH ₂ ); 3.23-3.17 (m, 2H, 1/2 CH ₂ + CH); 2.74-2.70 (m, 2H, CH ₂ ); 2.30 (s, 3H, CH ₃ ); 2.11 (s, 3H, CH ₃ ); 1.12 (s, 6H, 2xCH ₃ ). ¹³ C NMR (D ₂ O) δ 168.7; 139.5; 133.4; 132.8; 130.5; 126.8; 123.7; 54.5; 43.7; 37.0; 25.6; 19.4; 12.3. Anal. (C ₁₃ H ₁₈ N ₂ , HCl) C, H, N.

Hydrochloride Indan - 5 - yl - (4 - methyl - 4, 5 - dihydro - 3H - pyrrol - 2 - yl) - amine (22). (not included in the invention

¹ H NMR (D ₂ O) δ 7.26 (d, 1H, Har, J = 8.0); 7.08 (d, 1H, 1H, J = 1.5); 6.96 (dd, 1H, H, J = 1.9, J = 7.9); 4.03 (h, 1H, CH, J = 6.6); 2.97-2.93 (m, 2H, CH ₂ ); 2.80 (t, 4H, 2xCH ₂ , J = 7.5); 2.35-2.29 (m, 1H, 1/2 CH ₂ ); 1.97 (qn, 2H, CH ₂ , J = 7.5); 1.79-1.71 (m, 1H, 1/2 CH ₂ ); 1.16 (d, 3H, CH ₃ , J = 6.4). ¹³ C NMR (D ₂ O) δ 167.7; 145.7; 145.1; 132.7; 125.5; 121.9; 120.1; 56.9; 32.3; 32.0; 30.4; 28.0; 25.3; 19.8. Anal. (C ₁₄ H ₁₈ N ₂ , HCl) C, H, N.

Hydrochloride (5,6,7,8-tetrahydro-naphthalen-1-yl) - (4-Methyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (23). (not included in the invention

¹ H NMR (D ₂ O) δ 7.17 (d, 2H, Har, J = 7); 7.03 (t, 1H, H, J = 7.1); 4.07-3.99 (m, 1H, CH); 3.04-2.96 (m, 2H, CH ₂ ); 2.72 (t, 2H, CH ₂ , J = 5.7); 2.51 (t, 2H, CH ₂ , J = 5.9); 2.39-2.33 (m, 1H, 1/2 CH ₂ ); 1.81-1.61 (m, 5H, 1/2 CH ₂ + 2xCH ₂ ); 1.15 (d, 3H, CH ₃ , J = 6.4). ¹³ C NMR (D ₂ O) δ 168.6; 140.1; 133.9; 133.0; 130.2; 126.6; 123.6; 56.6; 29.9; 28.9; 28.2; 24.1; 22.1; 22.0; 19.8. Anal. (C ₁₅ H ₂₀ N ₂ , HCl) C, H, N.

Hydrochloride Indan-4-yl- (5,5-dimethyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (24). (no

included in the invention ¹ H NMR (D ₂ O) δ 7.27 (t, 1H, Har, J = 8); 7.19 (d, 1H, H, J = 7.5); 7.01 (d, 1H, H, J = 7.6); 3.08 (t, 2H, CH ₂ , J = 7.9); 2.88 (t, 2H, CH ₂ , J = 7.5); 2.76 (t, 2H, CH ₂ , J = 7.6); 2.13-1.95 (m, 4H, 2xCH ₂ ); 1.27 (s, 6H, 2xCH ₃ ). ¹³ C NMR (D ₂ O) δ 166.7; 147.5; 140.3; 130.6; 127.9; 125.0; 122.7; 64.7; 34.3; 32.6; 30.0; 29.7; 26.8; 24.8. Anal. (C ₁₅ H ₂₁ ClN ₂ , HCl) C, H, N.

Hydrochloride (3-Chloro-2-methyl-phenyl) - (5,5-dimethyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (25). ( not included in the invention

¹ H NMR (D ₂ O) δ 7.40 (d, 1H, Har, J = 7.9); 7.21 (d, 1H, Hr, J = 7.9); 7.18 (t, 1H, H, J = 7.8); 3.08 (t, 2H, CH ₂ , J = 7.6); 2.19 (s, 3H, CH ₃ ); 1.95 (t, 2H, CH ₂ , J = 7.8); 1.26 (s, 6H, 2xCH ₃ ). ¹³ C NMR (D ₂ O) δ 166.7; 135.5; 133.4; 130.1; 128.1; 125.3; 65.0; 37.4; 29.6; 26.8; 24.9. Anal. (C ₁₃ H ₁₇ ClN ₂ , HCl) C, H, N.

Hydrochloride (2,3-Dimethyl-phenyl) - (4,4-dimethyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (26). (not included in the invention

¹ H NMR (D ₂ O) δ 7.24 (d, 1H, H f, J = 7.6); 7.17 (t, 1H, H, J = 7.7); 7.06 (d, 1H, H, J = 7.6); 3.32 (s, 2H, CH ₂ ); 2.87 (s, 2H, CH ₂ ); 2.25 (s, 3H, CH ₃ ); 2.09 (s, 3H, CH ₃ ); 1.16 (s, 6H, 2xCH ₃ ). ¹³ C NMR (D ₂ O) δ 168.7; 139.5; 133.4; 132.8; 130.5; 126.8; 123.7; 59.2; 43.7; 37.0; 25.6; 19.4; 12.3. Anal. (C ₁₄ H ₂₀ N ₂ , HCl) C, H, N.

Hydrochloride (3-Chloro-2-methyl-phenyl) - (4,4-dimethyl-4,5-dihydro-3 H -pyrrol-2-yl) -amine (27). (not included in the invention

¹ H NMR (D ₂ O δ 7.45 (d, 1H, H 1, J = 7.9), 7.25 (d, 1H, Har, J = 7.9), 7.20 (t, 1H, Har, J = 7.8), 3.70 (m, 1H, 1/2 CH ₂ ), 3.19 (m, 2H, 1/2 CH ₂ + CH), 2.74 (m, 2H, CH); _2); 2.22 (s, 3H, CH _3); 1.10 (d, 3H, CH _3, J = 6.5) ¹³ C NMR (D ₂ O) δ 169.1,. 135.5; 133.4, 130.1, 128.1, 125.3, 54.2, 37.9, 29.5, 18.1, 14.2, Anal (C ₁₃ H ₁₇ ClN ₂ , HCl) C, H, N.

DESCRIPTION OF THE FIGURES

• The Figure 1A presents competition studies of [ ¹²⁵ I] -PIC binding in 3T3 cell membranes and 1B presents competition studies of [ ¹²⁵ I] -PIC binding in PC12 cell membranes performed according to the example 1.3. Each point is the average of 2 to 4 experiments performed in triplicate.
• Figure 1A : the ordinate axis represents the specific binding to [ ¹²⁵ I] PIC and the abscissa axis represents the log [M] in clonidine (square) and compound 1 according to the invention (triangles).
• Figure 1B : the ordinate axis represents the specific binding to [ ¹²⁵ I] PIC and the abscissa axis represents the log [M] of compound 1.
• The figure 2 shows the effect of the compound 1 according to the invention at the dose of 3 μmol / l on the secretion of adiponectin measured in the absence or in the presence of efaroxan at a dose of 100 μmol / l according to Example 1.4 .
  *** p <0.001 compared to the control; ### p <0.001 with respect to compound 1.
  • The ordinate axis represents the adiponectin secretion expressed in ng / ml / mg proteins.
  • The x-axis is from left to right: black histogram: control group, white histogram: Efaroxan treated group (100 μmol / ml), gray histogram: compound 1 treated group (3 μmol / ml), and hatched histogram : group treated with compound 1 (3 μmol / ml) + Efaroxan (100 μmol / ml).
• The figure 3 represents the list of systems on which the displacement of the specific binding by compound 1 was measured according to Example 3.
• The Figures 4A to 4C present the effects of acute treatment with compound 1 at a dose of 10 mg / kg (iv) on the hemodynamic parameters and sympathetic activity of urethane-anesthetized Sprague-Dawley rats (1.5 g / kg, ip) according to example 4.
• The Figure 4A presents the variation of sympathetic renal activity as a function of time.
  • Y axis: measurement of kidney sympathetic activity.
  • X axis: time in minutes (the arrow shows the time of administration of compound 1).
• The Figure 4B presents the variation of arterial pressure in mm Hg as a function of time. Black circles represent mean arterial pressure; the black diamonds pointed upwards represent the systolic blood pressure and the black diamonds point downwards represent the diastolic blood pressure.
  • Y-axis: Measurement of systolic (PAS) and diastolic (MAP) mean arterial pressure (MAP).
  • X axis: time in minutes (the arrow shows the time of administration of compound 1).
• The figure 4C shows the change in heart rate (HR) in bpm as a function of time.
  • Y-axis: heart rate (HR) expressed in beats per minute (bpm)
  • X axis: time in minutes (the arrow shows the time of administration of compound 1).
• The Figures 5A and 5B the effects of chronic treatment with compound 1 (20 mg / kg / day in drinking water) on body weight ( Figure 5A ) and the consumption of food ( Figure 5B ) in SHHF ( spontaneously hypertensive , heart failure, spontaneously hypertensive , cardiac insufficiency ) rats during the 12 weeks of treatment measured in accordance with Example 5.
• Figure 5A : ordinates: body weight in grams; abscissa: time in weeks.
  The black squares represent the controls and the black circles represent the group treated with the compound 1. ***: p <0.001 (ANOVA 2 factors).
• Figure 5B : ordinates: food consumption in grams / rat / day; abscissa: time in weeks.
  The black squares represent the controls and the black circles represent the group treated with the compound 1. ***: p <0.001 (ANOVA 2 factors).
• The Figures 6A and 6B effects of 12 weeks of treatment with compound 1 (20 mg / kg / day in drinking water) on blood pressure ( Figure 6A ) and heart rate ( Figure 6B ) in SHHF rats measured according to Example 5.
  At the end of the treatment, the SHHF rats were anesthetized with sodium pentobarbital (50 mg / kg / i, p,) tracheotomized and ventilated with ambient air.
  Blood pressure and heart rate were recorded through a catheter inserted into the left femoral artery.
• Figure 6A : ordinates: arterial pressure in mm Hg; from left to right: diastolic blood pressure (DBP), systolic blood pressure (SBP) and mean arterial pressure (MAP). The black histograms represent the control group, the blank histograms represent the group treated with the compound 1. *: p <0.05 (Student's t-test).
• Figure 6B : ordinate: heart rate (HR) expressed in beats per minute (bpm); the black histogram represents the control group, the white histogram represents the group treated with the compound 1.
• The Figures 7A to 7C represent the effects of a 12-week treatment with compound 1 (20 mg / kg / day in drinking water) on plasma total cholesterol ( Figure 7A ), triglycerides ( Figure 7B ) and free fatty acids ( Figure 7C ) in plasma of SHHF rats measured according to Example 5.
  At the end of treatment, SHHF rats were anesthetized with isoflurane (2.5%) after fasting for 18h and blood samples were obtained from the tail vein.
• Figure 7A : ordinates: total cholesterol (mmol / l); black histogram: control group and white histogram: group treated with compound 1. ****: p <0.0001 (Student's t-test).
• Figure 7B : ordinates: triglycerides (mmol / l); black histogram: control group and white histogram: group treated with compound 1. **: p <0.01;
• Figure 7C : ordinates: free fatty acids (mmol / l); black histogram: control group and white histogram: group treated with compound 1.
• The Figures 8A to 8G represent the effects of the 12-week treatment with compound 1 (20 mg / kg / day in drinking water) on glucose metabolism in SHHF rats measured according to Example 5.
  At the end of treatment, SHHF rats were anesthetized with pentobarbital sodium (50 mg / kg, ip) after 18 h of fasting. The left femoral vein was catheterized to collect blood samples for different dosages. To perform the glucose tolerance test, a glucose solution (0.5 g / kg, iv) was administered and plasma glucose concentrations were determined after 3, 6, 10, 15, 30 and 45 minutes.
• Figure 8A : ordinates: glucose (mmol / l); black histogram: control group, white histogram: group treated with compound 1.
• Figure 8B : ordinates: insulin (ng / ml); black histogram: control group, white histogram: group treated with compound 1. ****: p <0.0001 (Student's t test).
• Figure 8C : ordinates: (HOMA index of insulin resistance); black histogram: control group, white histogram: group treated with compound 1. ****: p <0.0001 (Student's t test).
• Figure 8D : ordinates: glucagon; black histogram: control group, white histogram: group treated with compound 1. *: p <0.05 (Student's t-test).
• Figure8E : ordinates: adiponectin (μg / ml); black histogram: control group, white histogram: group treated with compound 1. ****: p <0.0001 (Student's t-test).
• Figure 8F : ordinates: time in minutes (black squares: control group, white circles: group treated with compound 1.
• Figure 8G : ordinates: Area under the curve (AUC) after the glucose tolerance test; black histogram: control group, white histogram: group treated with compound 1.
  ***: p <0.001 (Student's t test).
• Figure 9 gives the pharmacological effects of compounds 1-27 of the invention on mean arterial pressure (MAP) and heart rate (HR) in anesthetized normotensive rat measured according to Example 6.

PHARMACOLOGICAL PART EXAMPLE 1 In Vitro Experiments 1.1 Cell culture

The murine 3T3-L1 preadipocytes were cultured at confluence at 37 ° C in DMEM medium containing 4.5 g / liter of D-glucose, 10% FCS, and antibiotics. At confluence, the differentiation of 3T3-L1 adipocytes was initiated by adding for 48 hours a mixture containing 100 μM methyl isobutylxanthine, 100 nM dexamethasone, and 175 nM insulin. The cells were then re-transplanted every 2-3 days with DMEM, 10% FCS and 175 nM insulin. More than 95% of the cells have the mature adipocyte phenotype, 10 days after confluence has been reached.

The PC-12 cells are cultured in 75-cm ² dishes in a DMEM medium (1000 mg / l glucose) supplemented with 10% inactivated FBS by treatment at 56 ° C., 100 U / ml penicillin and 100 μg / ml streptomycin . When the cells reached confluency (3-4 days after the start of the culture), they were harvested and subcultured by 0.25% trypsin for 2 minutes at 37 ° C. For specific binding studies, the medium is removed and the cells are stored by freezing at -20 ° C until used for the membrane preparation.

1.2 Membrane Preparations and Cell Extracts

The adipocytes were washed twice with ice-cold PBS, harvested and homogenized in 25 mM Tris-HCl buffer, pH 7.5, 1 mM EDTA. The homogenates were centrifuged at 20,000 xg for 15 min at 4 ° C, and the supernatant was stored at -80 ° C until use. The pellets were resuspended in 25 mM Tris-HCl buffer, pH 7.5, 1 mM EDTA, and stored at -80 ° C. Aliquots of the homogenates and supernatants were used to determine the protein content (BC Assay Uptima Kit, Interchim, Montlucon, France), using the BSA protein as standard.

The frozen PC12 cells are scraped from ice-cold Tris-HEPES buffer (5 mM Tris-HEPES, pH 7.7, 0.5 mM EDTA, 0.5 mM EGTA, and 0.5 mM MgCl ₂ ) and homogenized with a Potter. After centrifugation at 75,000 g for 20 min, the pellet is washed with ice-cold Tris-HEPES buffer and then centrifuged again. This last operation is performed twice. The pellets are resuspended in the same buffer at a concentration of 1 to 2 mg of protein / ml. Membrane preparations are stored at -80 ° C until use.

1.3 Binding Test with Compound 1 on Membrane Adipocyte Preparations and PC12 Cells 1.3.1. Operating mode

Competitive specific binding assays were performed using 0.5 nM [ ¹²⁵ I] -PIC in the presence of 10μM rauwolscine for 3T3 cell membranes or in the absence of rauwolscine for PC12 cells and 6 different concentrations of the ligand to be studied from 10 ^-9 to 10 ^-4 M.

The incubation was initiated by adding membranes of 3T3 cells (10-26 μg of proteins) or of PC12 cells (10-25 μg of proteins) in a final volume of 250 μl of Tris-HEPES buffer (50 mM Tris-HEPES pH 7.7, 0.5mM EDTA, 0.5mM EGTA and 0.5mM MgCl ₂ ) and was carried out at 25 ° C for 45 min.

The reaction was stopped by rapid vacuum filtration through 0.3% PEI-treated GF / B glass fiber filters with a Brandel® type filtration apparatus followed by three rapid filter washes with 3 ml of Tris buffer. 50 mM ice-cold HCl, pH 7.4. The radioactivity retained on the dried filters was determined by a Minaxi gamma counter (Packard, Meriden, CT, U, S, A,). Nonspecific binding was determined by the binding of [ ¹²⁵ I] PIC in the presence of 10 μM PIC, and represents approximately 43% of the total radioactivity. The choice of 10 μM PIC comes from pilot experiments showing that at this concentration, the residual binding obtained with the PIC was similar to that obtained with clonidine.

1.3.2. Results

The results are presented on the figure 1 .

Specific binding of 0.5 nM [ ¹²⁵ I] -PIC was measured. It ranges from 2633 to 6652 cpm in the membrane preparation of 3T3 adipocytes and 2100 to 3400 cpm in the membrane preparation of PC12 cells.

In adipocyte membrane preparations (3T3), clonidine, a reference molecule for RI ₁ , is able to displace [ ¹²⁵ I] -PIC specific binding in the preparation of 3T3 cell membranes with two affinities (IC ₅₀ = 54.9 ± 5.4 nM (57% of the total sites) and 8144 ± 426 nM, n = 2) demonstrating the presence of the receptor I ₁ in the preparation of membranes 3T3-L1. In addition, the selective compound 1 displaces the specific [ ¹²⁵ I] -PIC binding on the I ₁ receptor at a high affinity site (IC ₅₀ = 104 ± 7 nM (n = 4)) ( Figure 1A )).

In membrane preparations of PC12 cells, compound 1 selective receptor I ₁ displaces the specific binding of ^[125 I] -PIC with two affinities (high affinity IC ₅₀ = 3.2 ± 0.7 nM (55%) and low affinity 30698 + 5433 nM n = 2) as shown in fig.1 B .

The affinity for the α _2A -adrenergic receptor has been studied (see Table I in 2.2). No significant displacement was observed at the concentration of 10 ^-5 M.

The affinities of compound 1 for more than 50 receptors and transporters have been determined. Compound 1 has no similar affinity to that for the imidazoline I receptor ₁ ( figure 3 ).

1.4 Adiponectin production 1.4.1. Operating mode

To determine the adiponectin secretion by mature adipocytes, differentiated 3T3-L1 adipocytes (10 days after confluence) are cultured in 12-well plates and washed three times with DMEM, then cultured for 6 h in DMEM alone. in the absence or in the presence of 3 μM of compound 1. In certain wells, the selective imidazoline I ₁ , efaroxan receptor antagonist (100 μM) was added 30 min before exposure to compound 1.

The culture medium was then collected, centrifuged for 3 min at 10,000g to remove cellular contaminants, and the supernatant was stored at -80 ° C until use. After two washes with cold PBS, the adipocytes were collected in PBS, homogenized, and stored at -80 ° C. An aliquot of adipocyte homogenate was retained for protein determination. Adiponectin was measured by an ELISA kit according to the supplier's recommendations. Adiponectin concentration was normalized with cellular protein content.

1.4.2. Results

The results are presented figure 2 .

Compound 1 at a dose of 3 μmol / l induces an increase in adiponectin secretion by 3T3-L1 adipocytes (378 ± 38 vs 212.6 ± 19.1 ng / ml / mg protein p <0.001). Pre-incubation with efaroxan, a selective I ₁ receptor antagonist at a dose of 100 μmol / l, antagonizes the increase in adiponectin secretion (236 ± 19.2 vs 378 ± 38 ng / ml / mg protein, p <0.001) while efaroxan alone, at the same dose, has no significant effect compared to the control (175.2 ± 15.5 vs 212.6 ± 19.1 ng / ml / mg protein, p> 0.05).

EXAMPLE 2 Specific binding study on human platelets 2.1 Operating procedure 2 . 1 . 1 . Specific binding study of the I ₁ receptor.

The binding assays were performed at 37 ° C using [ ¹²⁵ I] LNP 911 radioligand according to the general procedure described but adapted to washed whole platelets ( Greney, H .; Urosevic, D .; Schann, S ,; Dupuy, L .; Bruban, V .; Ehrhardt, J, -D; Bousquet, P .; Dontenwill, M. [125 I] 2- (2-chloro-4-iodo-phenylamino) -5-methyl-pyrroline (LNP911), High-Affinity Radioligand Selective for Imidazoline Receptors. Mol. Pharmaco /. 2002, 62, 181-191 ).

The incubation was initiated by addition of 900 to 950 μl of platelet suspension at a concentration of 500,000 / μl in a final volume of 1 ml of Tyrode albumin and was carried out at 37 ° C. for 5 minutes (equilibrium conditions). ). The competition assays were performed using a single concentration of radioligand (50 μM, 200,000 cpm), in the presence of increasing concentration of appropriate unlabeled ligand. Nonspecific binding was determined by the binding of [ ¹²⁵ I] LNP 911 in the presence of 100 nM unlabeled LNP 911 and represents about 10% of the total radioactivity when 50 μM [ ¹²⁵ I] LNP 911 is used.

The reaction was stopped by rapid filtration under vacuum through GF / C glass fiber filters followed by five rapid filter washes with 3 ml of ice-cold Tyrode (137 nM NaCl, 2.7 nM KCl, 12 nM NaHCO ₃ , 0.36 nM NaH ₂ PO ₄ , pH 7.35). The radioactivity was measured on a gamma counter (Wallac 1410).

2.1.2 α ₂ adrenergic receptor binding study.

The membrane preparation was carried out as described by Newman-Tancredi, A; Nicolas, J, -P .; Audinot, V ,; Gavaudan, S ,; Verriele, L .; Touzard, M .; Chaput, C .; Richard, N ,; Millan, NJ (Action of alpha2 Adrenoreceptor Ligands at alpha2A and 5-HT1A Receptors: Antagonist, Atipamezole, and the Agonist, Dexmedetomidine, are Highly Selective for Alpha2A Adrenorecptors, Naunyn-Schmiedeberg's Arch Pharmacol 1998, 358, 197-206. ).

These membranes (30 μg proteins / ml for CHO-hα _2A and CHO-hα _2B , 100 μg protein / ml for CHO-hα _2C ) were incubated for 60 min at room temperature in a buffer of binding (33 mM Tris HCl, 1 mM EDTA, pH 7.5) in a final volume of 500 μL containing 0.8 or 1 or 2 nM [ ³ H] RX821002 respectively for the adrenergic receptors hα _2A , hα _2B and hα _2C .

Incubation was stopped by rapid filtration under vacuum through GF / C glass fiber filters followed by three successive washes with ice-cold binding buffer.

Nonspecific binding was determined by 10 μM phentolamine.

2.2 Results

Competition tests were analyzed by nonlinear regression using the GraphPad program

K i were determined using the method of Cheng and Prussof ( Cheng, Y. C .; Prusoff, WH Relationship between Constant Inhibition (Ki) and the Inhibition Concentration of Inhibition (I50) of an Enzymatic Reaction. Biochem. Pharmacol. 1973, 22.3099-3108 ).
The results are shown in Table I below: <b> TABLE I </ b> compounds I ₁ Ki (M) # α ₂ Ki (M) ^§ 1 8.1 × 10 ^-9 > 10 ^-5 5 1.9 × 10 ^-8 > 10 ^-5 8 2.2 × 10 ^-10 > 10 ^-5 9 2.8 × 10 ^-9 > 10 ^-5 13 (comparative) 1,2 × 10 ^-7 > 10 ^-5 20 2.8 × 10 ^-9 > 10 ^-5 # measured on platelets with [ ¹²⁵ I] LNP 911, except for compound 13, the measurement of which is carried out on PC12 cells with [ ¹²⁵ I] PIC;
Measured on CHO cells with phentolamine.

The results presented above clearly show the specificity of the compounds of the invention for the imidazoline type 1 receptor relative to α ₂ adrenergic receptors.

EXAMPLE 3 Specific binding study of compound 1 on different receptors, transporters and enzymes 3.1. Operating mode

Compound 1 was tested at two concentrations 10 ^-7 (1.0E-07) M and 10 ^-5 M (1.0E-05) on different receptors, transporters and enzymes according to techniques described in the literature and adapted to the laboratory.

3.2. Results

They are given in the table of the figure 3 .

The results presented above clearly show that compound 1 does not bind to any of the receptors, transporters and enzymes tested with an affinity similar to that of compound 1 for IRs ₁ .

EXAMPLE 4 Measurement of Sympathetic Nerve Renal Activity (RSNA): Effect of Acute Treatment with Compound 1 at 10 mg / kg (i.v.) on Hemodynamic Parameters and Sympathetic Activity 4.1. Operating mode

Male Sprague-Dawley rats (10 weeks old, Charles River Laboratories, L'Arbresle, France) were anesthetized with urethane (1.5 g / kg ip, supplemented with 0.1 g / kg iv if needed) and placed on a heating blanket to maintain rectal temperature at 37 ° C. Catheters were inserted into the lower abdominal aorta and inferior vena cava for measurement of arterial pressure and compound administration respectively.

The left renal nerve was carefully isolated and a major branch of the nerve was placed on a platinum-iridium bipolar electrode and isolated with silicone gel (604A and B, Wacker Chemie, Munich, Germany). Throughout the experiment, the rat was ventilated using a tracheal cannula (7-8 ml / kg X 72 cycles / min) with a mixture of oxygen and air (~ 8% -20% ).

Blood pressure was measured by connecting the arterial catheter to a pressure transducer (TNF-R, Ohmeda, Bilthoven, Holland) coupled to an amplifier (model 13-4615-52, Gould, Cleveland, OH).

Renal sympathetic nerve (ANSR) activity was amplified (X50,000), filtered bandwidth (300-3,000 Hz: Model P-511J, Grass, Quincy, MA), and ground by a home-made analog rectifier including a low frequency filter with a cutoff frequency of 150 Hz.

Both parameters were recorded continuously using a computer equipped with a digital analog converter (AT-MIO-16 model, National Instruments, Austin, TX), and LabVIEW 5.1 software (National Instruments).

Blood pressure and ANSR were recorded before (baseline) and after administration of compound 1 (10 mg / kg, i.v.). At the end of the recording session, chlorisondamine, a ganglion blocker, was administered (2.5 mg / kg iv) to assess the level of background that was then subtracted from all ANSR data for the following analyzes. At the end of the experiment, the rats were euthanized with an intravenous overdose of pentobarbital sodium.

4.2. Results

The results are presented Figures 4A to 4C .

Compound 1, at a dose of 10 mg / kg, iv, causes a 50% decrease in renal sympathetic activity ( Figure 4A ).

In parallel, compound 1 at the same concentration causes a sharp decrease in blood pressure (PAS: 105.3 ± 3 vs 141.7 ± 2.3 mmHg, p <0.001; WFP: 77.4 ± 3.6 vs 108 ± 3.4 mmHg, p <0.0001, PAD: 58.6 ± 3.4 vs 83.2 ± 4 mmHg, p <0.001) and heart rate (288.4 ± 10.3 vs 331, 4 ± 14 bpm, p <0.01) ( Figures 4B and 4C ). The decrease in kidney sympathetic activity, blood pressure and heart rate lasts more than one hour.

EXAMPLE 5 Measurement of blood pressure, heart rate, plasma biochemical parameters and glucose metabolism: Effect of chronic treatment with compound 1 at a dose of 20 mg / kg / day for 12 weeks 5.1. Operating mode 5.1.1 Animals

SHHF male rats (spontaneously hypertensive heart failure; spontaneously hypertensive heart failure) aged 12 weeks were used in this study (Center for Breeding Charles River, L'Arbresle, France).

The animals were placed in a controlled temperature and light room with free access to tap water and were fed a standard diet (A04, SAFE, Augy France). This study was conducted in accordance with the institutional recommendations and rules formulated by the European Community for the use of experimental animals (L358-86 / 609 / EEC).

5.1.2 Chronic treatment with compound 1

Compound 1 was administered in drinking water for 12 weeks at a dose of 20 mg / kg / day (n = 17). Water consumption is measured regularly to adjust the concentration of compound 1. Untreated control SHHF rats drank normal water (n = 10).

Body weight, water intake and food were measured daily. After 12 weeks of treatment, blood samples were taken. Three days later, blood pressure and heart rate were recorded and a glucose tolerance test was performed.

5.1.3. Recording of blood pressure and heart rate

Rats were anesthetized with pentobarbital 50 mg / kg, ip (Céva Animal Health, Libourne, France) and tracheotomized. The vein and femoral artery were catheterized for substance administration and blood pressure measurement respectively. The rats were ventilated with ambient air and paralyzed by administration of pancuronium bromide (1.5 mg / kg, iv, Organon SA, France). Blood pressure was recorded after stabilization with a pressure transducer (Gould P23XL) and a recorder (Gould electronics BS 272, Longjumeau, France). Mean arterial pressure (MAP) was calculated as the pressure diastolic plus one third of the differential blood pressure. The heart rate was also recorded from the pressure signal with a Gould Biotach amplifier (model 13-4615-66).

The results are presented in the Figures 6A and 6B .

After 12 weeks of treatment at 20 mg / kg / day with compound 1 in drinking water, the blood pressure of SHHF rats was significantly decreased (153 ± 7 vs 176 ± 6 mmHg, p <0.05 ) ( Figure 6A ), but the heart rate is not changed (367 ± 6 vs 361 ± 8 bpm, p> 0.05) ( Figure 6B ).

5.1.4 Measurement of plasma biochemical parameters

After 12 weeks of treatment, blood samples were obtained from caudal tail vein of anesthetized rats (2.5% isoflurane, Abbott, Rungis, France) after fasting 18h.

The blood samples were centrifuged for 15 minutes at 2000 g and the plasma was frozen at -80 ° C until glucose, total cholesterol, HDL and LDL cholesterol, and fatty acids were measured. These assays were carried out on the "Biological Technical Plateau of the Strasbourg University Hospitals" (Advia 2400, Bayer HealthCare).

Insulin, leptin, adiponectin and glucagon were assayed by ELISA kits (insulin: Mercodia, Uppsala, Sweden, Leptin: Yanaihara Institute Inc. "Shizuoka, Japan adiponectin: B-Bridge International, Mountain View, USA and glucagon: Gentaur, Kampenhout, Belgium) according to the supplier's recommendations.

The results are presented Figures 7A to 7C and Figures 8A to 8E .

After 12 weeks of treatment with Compound 1, a significant decrease in total plasma cholesterol was observed (2.7 ± 0.09 vs 3.8 ± 0.18 mmol / l, P <0.0001) ( Figure 7A ). Compound 1 also causes a decrease in plasma triglyceride concentration (3.8 ± 0.25 vs 4.59 ± 0.23 mmol / l, p <0.01) ( Figure 7B ); free fatty acids are unaffected by the treatment ( Figure 7C ).

Fasting blood glucose is not affected by treatment ( figure 8A ), but fasting plasma insulin was significantly decreased (15.2 ± 2 vs 46.8 ± 3.7 ng / ml, p <0.0001) ( Figure 8B ).

The calculation of the HOMA-IR index confirms that the treated SHHF rats have better insulin sensitivity than the control SHHF rats (110 ± 14 vs 534 ± 38, p <0.0001) ( Figure 8C ). Finally, compound 1 causes a significant drop in glucagon (77.3 ± 14 vs 161.3 ± 33 μg / ml, p <0.05) (FIG. 6D) and a sharp increase in plasma adiponectin concentration (10, 6 ± 0.52 vs 5.54 ± 0.14 μg / l, p <0.0001) ( figure 8E ).

5.1.5 Glucose Tolerance Test (IVGTT)

A glucose solution at 0.5 g / kg was administered intravenously. Plasma glucose concentration was assessed using a blood glucose meter before injection to fasted animals for 18h, then 3, 6, 10, 15, 30, and 45 min after glucose administration (Accu Check Go, Roche Diagnostics , Meylan, France). The areas under the curves (AUC) were then determined to compare the groups.

5.2. Results 5.2.1 Measurement of body weight and food consumption

Results on weight and food consumption are presented Figures 5A and 5B .

After 9 weeks of treatment and until the end of treatment, SHHF rats treated with compound 1 had a lower body weight than controls; their food consumption is already lower than that of controls after one week of treatment ( Figures 5A and 5B ).

5.2.2. Measurement of plasma biochemical parameters

The results are presented Figures 7A to 7C and Figures 8A to 8E .

After 12 weeks of treatment with Compound 1, a significant decrease in total plasma cholesterol was observed (2.7 ± 0.09 vs 3.8 ± 0.18 mmol / l, P <0.0001) ( Figure 7A ). Compound 1 also causes a decrease in plasma triglyceride concentration (3.8 ± 0.25 vs 4.59 ± 0.23 mmol / l, p <0.01) ( Figure 7B ); free fatty acids are unaffected by the treatment ( Figure 7C ).

Fasting blood glucose is not affected by treatment ( figure 8A ), but fasting plasma insulin was significantly decreased (15.2 ± 2 vs 46.8 ± 3.7 ng / ml, p <0.0001) ( Figure 8B ).

The calculation of the HOMA-IR index confirms that the treated SHHF rats have better insulin sensitivity than the control SHHF rats (110 ± 14 vs 534 ± 38, p <0.0001) ( Figure 8C ). Finally, compound 1 causes a significant drop in glucagon (77.3 ± 14 vs 161.3 ± 33 μg / ml, p <0.05) (FIG. 6D) and a sharp increase in plasma adiponectin concentration (10, 6 ± 0.52 vs 5.54 ± 0.14 μg / l, p <0.0001) ( figure 8E ).

5.2.3. Glucose Tolerance Test (IVGTT)

The results are presented Figures 8F and 8G .

Compound 1 increases the glucose tolerance of SHHF rats (AUC: 556 ± 20 vs 710 ± 37 mmol.min / l, p <0.001) ( Figures 8F and 8G ).

EXAMPLE 6 Measurement of Blood Pressure and Heart Rate: Effect of Acute Intravenous or Intravenous Treatment 6.1. Operating mode

Male adult Wistar rats were anesthetized with pentobarbital 50 mg / kg ip, and their physiological temperature was kept constant. The animals were tracheotomized and the left carotid was catheterized to allow iv administration Animals were paralyzed by administration of pancuronium bromide (1 mg / kg, iv, Organon SA, France) and ventilated with ambient air (Hugo Sachs electronic model 7025). A catheter was introduced into the left femoral artery and connected to a pressure transducer and recorder (Gould electronics BS 272, Longjumeau, France). Heart rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure (MAP) were continuously recorded from the pressure signal (Gould Biotach amplifier model 13-4615-66); [PAM = PAD +1/3 (PAS-PAD)]. Mean arterial pressure (MAP) and heart rate (HR) are measured for 90 minutes.

6.2. Results

The results are expressed as the maximum change in mean arterial pressure expressed in mm of mercury (mmHg) and heart rate expressed in beats per minute (bpm) compared to pre-treatment basal values. The percentage of corresponding variation is also determined. The results are considered significant when the variation is 10% higher than the base value.

In experiments where the drug is injected intractively, 0.2 ml of a drug solution is injected after removal of an identical volume of cerebrospinal fluid.

The results are presented in the table of the Figure 9 .

Claims (14)

1. Compounds of following general formula (I):

   

   wherein:

   a) either R12 represents H, and

   - R1 and R2 each independently are:

   a halogen, straight-chain or branched C1 to C8 alkyl, C2-C8 alkene, straight-chain or branched C1 to C8 alkoxy, C3-C6 cycloalkyl, C5-C6 bicycloalkyl, a polyether chain, C1-C5 perfluoroalkyl, C1-C8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO₂H, CO₂R' where R' is a straight-chain or branched C1-C8 alkyl or C3-C6 cycloalkyl; or
   R1 and R2 together form a C5 ring

   - R3, R4 and R5 each independently represent:

   a hydrogen, a halogen, straight-chain or branched C1 to C8 alkyl, C2-C8 alkene, straight-chain or branched C1 to C8 alkoxy, C3-C6 cycloalkyl, C5-C6 bicycloalkyl, a polyether chain, a C1-C5 perfluoroalkyl, C1-C8 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO₂H, CO₂R' where R' is a straight-chain or branched C1-C8 alkyl, or a C3-C6 cycloalkyl;

   - R6, R7, R9 and R11 represent hydrogens;

   - R8 and R10 are chosen from the group consisting of a hydrogen and straight-chain or branched C1 to C5 alkyl, at least one of the two being a straight-chain or branched C1 to C5 alkyl;

   b) or R12 represents CH(R13)(CH₂) and forms a C5 ring with R5, R13 representing H or CH₃,

   - R1, R2, R3 and R4 are chosen from the group consisting of a hydrogen, a halogen, straight-chain or branched C1 to C8 alkyl, C2-C8 alkene, straight-chain or branched C1 to C8 alkoxy, C3-C6 cycloalkyl, C5-C6 bicycloalkyl, a polyether chain, a C1-C5 perfluoroalkyl, C1-C8 acyl, -OH, -SH, a primary, secondary or tertiary amine, -CN, -CO₂H, -CO₂R' where R' is a straight-chain or branched C1-C8 alkyl, and a C3-C6 cycloalkyl;

   - R6, R7, R9 and R11 represent hydrogens;

   - R8 and R10 are chosen from the group consisting of a hydrogen and straight-chain or branched C1 to C5 alkyl, at least one of the two being a straight-chain or branched C1 to C5 alkyl,

   provided that at least one from among R1 and R13 is not a hydrogen;

   and the pharmacologically acceptable salts thereof.
2. The compounds according to claim 1 of following general formula (Ia):

   

   wherein:

   R3 and R12 are hydrogens;

   R8 and R10 are chosen from the group consisting of a hydrogen and straight-chain or branched C1 to C5 alkyl, at least one of the two being a straight-chain or branched C1 to C5 alkyl; and

   R4 and R5 are independently chosen from the group consisting of a hydrogen, halogen, straight-chain or branched C1 to C3 alkyl, straight-chain or branched C1 to C3 alkoxy, C1-C3 perfluoroalkyl, C1-C3 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO₂H and CO₂R' where R' is a straight-chain or branched C1-C3 alkyl, preferably from the group consisting of a halogen, straight-chain or branched C1 to C3 alkyl, straight-chain or branched C1 to C3 alkoxy, C1-C3 perfluoroalkyl and a C1-C3 acyl.
3. The compounds according to claim 2 wherein R4 and R5 are hydrogens.
4. The compounds according to claim 1 of following general formula (Ib):

   

   where:

   R12 is a hydrogen;

   R8 and R10 are chosen from the group consisting of a hydrogen and straight-chain or branched C1 to C5 alkyl, at least one of the two being a straight-chain or branched C1 to C5 alkyl;

   R1 and R2 are independently chosen from the group consisting of a halogen, straight-chain or branched C1 to C3 alkyl, straight-chain or branched C1 to C3 alkoxy, C1-C3 perfluoroalkyl and a C1-C3 acyl; and

   R3, R4 and R5 are independently chosen from the group consisting of a hydrogen, halogen, straight-chain or branched C1 to C3 alkyl, straight-chain or branched C1 to C3 alcoxy, C1-C3 perfluoroalkyl, C1-C3 acyl, OH, SH, a primary, secondary or tertiary amine, CN, CO₂H and CO₂R' where R' is a straight-chain or branched C1-C3 alkyl, preferably from the group consisting of a halogen, straight-chain or branched C1 to C3 alkyl, straight-chain or branched C1 to C3 alkoxy, C1-C3 perfluoroalkyl and a C1-C3 acyl.
5. The compounds according to claim 4 wherein R3, R4 and R5 are hydrogens.
6. The compounds according to claim 4 or 5 wherein R1 and R2 are independently chosen from the group consisting of a halogen and straight-chain or branched C1 to C3 alkyl.
7. The compound according to one of claims 1 to 6 chosen from among one of the following formulas:

   

   

   
8. The compounds according to claim 1 of following general formula (Ic):

   

   wherein:

   - R1, R2, R3 and R4 are chosen from the group consisting of a hydrogen, halogen, straight-chain or branched C1 to C3 alkyl, straight-chain or branched C1 to C3 alkoxy, C1-C3 perfluoroalkyl, C1-C3 acyl, OH, SH, a primary, secondary or tertiary amine, -CN, -CO₂H and -CO₂R' where R' is a straight-chain or branched C1-C3 alkyl;

   - R8 and R10 are chosen from the group consisting of a hydrogen and straight-chain or branched C1 to C5 alkyl, at least one of the two being a hydrogen, provided that at least one from among R1 and R13 is not a hydrogen.
9. The compounds according to claim 8 wherein:

   - R2, R3, R4 are hydrogens,

   - R13 is H and R1 is a halogen and straight-chain or branched C1 to C3 alkyl; or R13 is a methyl and R1 is chosen from the group consisting of a hydrogen, halogen and straight-chain or branched C1 to C3 alkyl; and

   - R8 and R10 are chosen from the group consisting of a hydrogen and straight-chain or branched C1 to C5 alkyl, at least one of the two being a hydrogen.
10. The compounds according to claim 8 or 9 chosen from among one of the following formulas:

    

    

    
11. The compounds such as defined in one of claims 1 to 10 for use in the prevention and/or treatment of metabolic syndrome.
12. A pharmaceutical composition comprising as active ingredient at least one compound according to one of claims 1 to 10 in association with a pharmaceutically acceptable vehicle.
13. A pharmaceutical composition according to claim 12 which can be administered via oral route.
14. A pharmaceutical composition which can be administered via oral route according to claim 13 wherein the dose of the active ingredient is between 1 mg/kg and 100 mg/kg in man.

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